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1.  The Role of Irreversible HER Family Inhibition in the Treatment of Patients with Non-Small Cell Lung Cancer 
The Oncologist  2011;16(11):1498-1507.
The clinical development of irreversible tyrosine kinase inhibitors that target the human epidermal growth factor receptor family in non-small cell lung cancer is reviewed.
Small-molecule tyrosine kinase inhibitors (TKIs) of the human epidermal growth factor receptor (HER) include the reversible epidermal growth factor receptor (EGFR/HER-1) inhibitors gefitinib and erlotinib. EGFR TKIs have demonstrated activity in the treatment of patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations; however, multiple mechanisms of resistance limit the benefit of these drugs. Although resistance to EGFR TKIs can be intrinsic and correlated with molecular lesions such as in Kirsten rat sarcoma viral oncogene homolog (KRAS; generally observed in a wild-type EGFR background), acquired resistance to EGFR TKIs can evolve in the setting of activating EGFR mutations, such as in the case of EGFR T790M mutations. Several irreversible inhibitors that target multiple members of the HER family simultaneously are currently in clinical development for NSCLC and may have a role in the treatment of TKI-sensitive and TKI-resistant disease. These include PF00299804, an inhibitor of EGFR/HER-1, HER-2, and HER-4, and afatinib (BIBW 2992), an inhibitor of EGFR/HER-1, HER-2, and HER-4. Results of large, randomized trials of these agents may help to determine their potential for the treatment of NSCLC.
doi:10.1634/theoncologist.2011-0087
PMCID: PMC3233283  PMID: 22016476
Irreversible EGFR/HER-2 tyrosine kinase inhibitors; Non-small cell lung cancer; Resistance; Afatinib (BIBW 2992); PF00299804
2.  Molecular predictors of response to tyrosine kinase inhibitors in patients with Non-Small-Cell Lung Cancer 
Introduction
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have become a treatment option in non-small-cell lung cancer (NSCLC) patients. However, despite their use in this disease, a significant number of patients will eventually develop resistance and relapse. In this study, we aimed to characterize several molecular events involved in potential resistance mechanisms to anti-EGFR treatment and correlate our findings with clinical outcome.
Material and methods
The medical records of patients with NSCLC who received anti-EGFR TKIs in any line within the participating centers were reviewed and available paraffin embedded tissue was retrieved. Mutational analysis for EGFR, KRAS, BRAF and intron-exon 14 deletions of MET; FISH analysis for chromosomal gain or amplification for EGFR, MET and the deletion marker D7S486 were performed. Furthermore, the expression of EGFR and MET were analysed by immunohistochemistry. All results were correlated with treatment outcomes.
Results
Between 10/2001 and 12/2009 from an initial cohort of 72 treated patients, 59 cases (28 gefitinib/ 31 erlotinib) were included in the analysis. The majority had adenocarcinoma histology (68%), and received treatment in the second line setting (56%). Disease control rate (DCR) was 25.4% for all patients. EGFR and RAS mutational rates were 33% and 10% respectively, no other mutations were identified. High EGFR expressing tumors were found in 7 of 45 cases and pEGFR positivity (IHC) was found in 56% of the cases; MET expression was found in 48% of tumors. EGFR gene amplification was found in 4 cases, two cases showed high polysomy; overall, 13% cases were FISH positive for EGFR. High polysomy of MET gene was detected in 1/43 cases tested. D7S486 locus deletion was detected in 15/37 (40%) of cases. EGFR mutational status and gene gain were both associated with more favorable DCR. No other associations between examined biomarkers and DCR or survival were noted.
Conclusions
EGFR mutational status is a predictor for disease control in patients with NSCLC treated with anti-EGFR TKIs. The predictive role of several other molecules involved in potential resistance to anti-EGFR TKIs is worthy of additional investigation.
doi:10.1186/1756-9966-31-77
PMCID: PMC3533816  PMID: 22992338
Predictive; Somatic mutation; EGFR; Gefitinib; Erlotinib; Response
3.  Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC 
OncoTargets and therapy  2013;6:135-143.
The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and gefitinib, are approved for use in the first-line setting in patients with known EGFR-activating mutations and in the second- and third-line settings for all NSCLC patients. These first-generation EGFR-TKIs improve progression-free survival when compared to chemotherapy in patients with EGFR-activating mutations in the first-line setting. However, nearly all patients develop resistance to EGFR-directed agents. There is a need for further therapy options for patients with disease progression after treatment with reversible EGFR-TKIs. Afatinib is an irreversible ErbB family blocker that inhibits EGFR, HER2, and HER4. In vitro and in vivo, afatinib have shown increased inhibition of the common EGFR-activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib. Clinically, afatinib has been evaluated in the LUX-Lung series of trials, with improvement in progression-free survival reported in patients with EGFR-activating mutations in both first- and second-/third-line settings when compared to chemotherapy. Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and EGFR-activating mutations.
doi:10.2147/OTT.S23165
PMCID: PMC3594037  PMID: 23493883
afatinib; EGFR; irreversible EGFR inhibitor; EGPR-TKIs; LUX lung; resistance mutation; targeted therapy
4.  Which biomarker predicts benefit from EGFR-TKI treatment for patients with lung cancer? 
British Journal of Cancer  2007;96(6):857-863.
Subsets of patients with non-small cell lung cancer respond remarkably well to small molecule tyrosine kinase inhibitors (TKI) specific for epidermal growth factor receptor (EGFR) such as gefitinib or erlotinib. In 2004, it was found that EGFR mutations occurring in the kinase domain are strongly associated with EGFR-TKI sensitivity. However, subsequent studies revealed that this relationship was not perfect and various predictive markers have been reported. These include EGFR gene copy numbers, status of ligands for EGFR, changes in other HER family genes or molecules downstream to EGFR including KRAS or AKT. In this review, we would like to review current knowledge of predictive factors for EGFR-TKI. As all but one phase III trials failed to show a survival advantage of the treatment arm involving EGFR-TKIs, it is necessary to select patients by these biomarkers in future clinical trials. Through these efforts, it would be possible to individualise EGFR-TKI treatment for patients suffering from lung cancer.
doi:10.1038/sj.bjc.6603665
PMCID: PMC2360106  PMID: 17325698
gefitinib; erlotinib; biomarker; clinical trials; individualized therapy
5.  The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations 
Gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), were the first molecularly targeted agents to become clinically available for the treatment of non-small cell lung cancer (NSCLC). During the course of their clinical development, it has become clear that the substantial clinical benefit associated with EGFR-TKIs is limited to patients harboring activating mutations of EGFR. Accumulating clinical outcomes in patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs support the notion that this group of individuals constitutes a clinically distinct population. These findings have prompted investigations of the potential role of first-line treatment with EGFR-TKIs in molecularly selected patients, with platinum-based doublet chemotherapy currently being the standard of care for most individuals with advanced NSCLC. This review summarizes the results of recent clinical trials of EGFR-TKIs in selected patients and highlights the efficacy of these drugs in first-line treatment as a form of personalized medicine aimed at improving therapy for advanced NSCLC.
doi:10.1177/1758834010370698
PMCID: PMC3126025  PMID: 21789142
epidermal growth factor receptor mutation; first-line treatment; non-small cell lung cancer; tyrosine kinase inhibitor
6.  BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations  
PLoS Medicine  2007;4(10):e315.
Background
Epidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process.
Methods and Findings
To study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis.
Conclusions
Our results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.
Susumu Kobayashi and colleagues provide evidence that the polypeptide BIM is involved in tyrosine kinase inhibitor (TKI)-induced apoptosis in sensitiveEGFR-mutant cells and suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.
Editors' Summary
Background.
Most cases of lung cancer—the leading cause of cancer deaths worldwide—are “non-small cell lung cancer” (NSCLC). Many patients with NSCLC die within a year of their diagnosis, but recently, “targeted” therapies have increased the life expectancy of some of them. Like all cancers, NSCLC occurs when cells begin to divide uncontrollably because of changes (mutations) in their genes. Targeted therapies specifically attack these changes and, unlike standard chemotherapy drugs, kill cancer cells without damaging normal cells. The targeted drugs used to treat NSCLC are gefitinib and erlotinib, two epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In normal cells, messenger proteins bind to EGFR and activate its tyrosine kinase, an enzyme that sticks phosphate groups on tyrosine (an amino acid) in other proteins. These “phosphorylated” proteins then tell the cell to divide. In some NSCLCs, EGFR drives uncontrolled cell division because its tyrosine kinase is mutated and the cancer becomes dependent on or “addicted” to EGFR signaling for its survival. TKI treatment can dramatically shrink this subset of NSCLCs, most of which lack a specific part of EGFR (the gene that encodes EGFR) or have the amino acid leucine instead of arginine at position 858 (an L858R mutation) of EGFR.
Why Was This Study Done?
TKI-sensitive NSCLCs eventually become resistant to TKIs because they acquire additional (secondary) mutations. In half of these TKI-resistant tumors, the additional mutation is replacement of threonine by methionine at position 790 (T790M) in EGFR. However, the mutations responsible for the remaining cases of TKI resistance are not known. In addition, little is known about how TKIs induce cell death other than that they induce a type of cell death called apoptosis. A better understanding of how TKIs kill tumor cells and how secondary mutations block their effects could reveal ways to enhance their action and improve the outcome for patients with NSCLC. In this study, the researchers have studied the mechanism of TKI-induced cell death and of resistance to TKIs.
What Did the Researchers Do and Find?
The researchers first measured the ability of gefitinib to cause apoptosis (genetically programmed cell death) in NSCLC cell lines (tumor cells adapted to grow indefinitely in dishes) that had the EGFR deletion, the L858R mutation, or normal EGFR. Gefitinib caused apoptosis only in cell lines with altered EGFR. Then they asked whether a proapoptotic protein called BIM (a member of the BCL2 family of pro- and antiapoptotic proteins) is involved in TKI-induced cell death—BIM is known to be involved in this process in leukemia (blood cancer) cells. Gefitinib treatment increased the expression of BIM in TKI-sensitive NSCLC cell lines and reduced the phosphorylation of BIM (which makes BIM more active). By contrast, blocking BIM expression using a technique called RNA interference reduced TKI-induced apoptosis in TKI-sensitive NSCLC cells. Furthermore, introduction of the T790M resistance mutation into these cells blocked gefitinib-induced up-regulation of BIM and apoptosis. Finally, the researchers identified a new TKI resistance mutation (L747S, substitution of serine for leucine at position 747) in a patient whose TKI-sensitive NSCLC had become resistant to gefitinib, and showed that this resistance mutation also reduced TKI-induced apoptosis in cells growing in dishes by interfering with BIM up-regulation.
What Do These Findings Mean?
These findings (and those reported by Gong et al. and Cragg et al.) show that BIM is required for TKI-induced apoptosis in EGFR mutant NSCLC cells. They also show that mutations that make TKI-sensitive cells resistant to these drugs reduce TKI-induced apoptosis by preventing the upregulation of BIM. These results were obtained by examining the behavior of established cell lines growing in dishes and need to be confirmed in cells freshly isolated from tumors and in tumors themselves. However, they suggest that the efficacy of TKIs could be increased by finding ways to increase BIM expression or to activate other proteins involved in apoptosis Such approaches might be particularly beneficial for patients with NSCLC whose initially TKI-sensitive tumors have acquired mutations that make them resistant to TKIs.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040315.
Ingo Mellinghoff discusses this paper and two related ones in a perspective article
US National Cancer Institute information for patients and professionals on lung cancer (in English and Spanish)
Information for patients from Cancer Research UK on lung cancer, including information on treatment with TKIs
CancerQuest information on all aspects of cancer from Emory University (in several languages)
Wikipedia pages on apoptosis, epidermal growth factor receptor, and BCL2 proteins (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Information for patients from Cancerbackup on erlotinib and gefitinib
doi:10.1371/journal.pmed.0040315
PMCID: PMC2043012  PMID: 17973572
7.  EGFR mutation: Significance as a stratification factor in the era of molecular-targeted therapy 
Oncology Letters  2011;2(2):383-387.
Somatic mutations of epidermal growth factor receptor (EGFR) are the strongest predictive markers for the response to EGFR-tyrosine kinase inhibitors (TKIs). Patients with EGFR mutations generally receive EGFR-TKI treatment, and their survival has been significantly improved compared with that before the development of EGFR-TKIs. This study aimed to clarify the impact of EGFR mutational status on the survival of patients with non-small cell lung cancer (NSCLC) receiving cytotoxic agents, but not EGFR-TKIs, as their first-line chemotherapy. In addition, we analyzed patients with EGFR mutations to determine whether the timing of EGFR-TKI administration affects overall survival (OS). A total of 83 NSCLC patients with stage IIIB/IV who received chemotherapy alone and whose EGFR mutational status was known were investigated. Univariate and multivariate analysis for OS was performed using parameters such as age, gender, performance status (PS), histology, disease stage, smoking status, EGFR mutational status and administration of a first-line regimen. Among the 52 patients with EGFR mutations who received EGFR-TKIs, OS between those who received EGFR-TKIs as their first-line treatment and after chemotherapy were similar. Among the 83 patients who received cytotoxic agents as their first-line chemotherapy, the multivariate analysis showed OS to be significantly associated with PS (p<0.001), histology (p=0.039) and EGFR mutational status (p=0.040). OS was almost similar among the 52 patients with EGFR mutations who received EGFR-TKIs in a first- and second-line setting (25.6 vs. 26.8 months, p=0.914). The EGFR mutational status had a significant impact on the survival of NSCLC patients, although these patients did not receive EGFR-TKIs as their first-line chemotherapy. In future randomized trials, even when EGFR-TKIs are not included in experimental regimens, patients may need to be stratified by EGFR mutational status in order that study results be evaluated appropriately.
doi:10.3892/ol.2011.240
PMCID: PMC3410597  PMID: 22866092
non-small cell lung cancer; chemotherapy; epidermal growth factor receptor; mutation; stratification factor
8.  Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors 
Oncogene  2009;28(Suppl 1):S24-S31.
The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), gefitinib and erlotinib, are reversible competitive inhibitors of the tyrosine kinase domain of EGFR that bind to its adenosine-5′ triphosphate-binding site. Somatic activating mutations of the EGFR gene, increased gene copy number and certain clinical and pathological features have been associated with dramatic tumor responses and favorable clinical outcomes with these agents in patients with non-small-cell lung cancer (NSCLC). The specific types of activating mutations that confer sensitivity to EGFR TKIs are present in the tyrosine kinase (TK) domain of the EGFR gene. Exon 19 deletion mutations and the single-point substitution mutation L858R in exon 21 are the most frequent in NSCLC and are termed ‘classical’ mutations. The NSCLC tumors insensitive to EGFR TKIs include those driven by the KRAS and MET oncogenes. Most patients who initially respond to gefitinib and erlotinib eventually become resistant and experience progressive disease. The point mutation T790M accounts for about one half of these cases of acquired resistance. Various second-generation EGFR TKIs are currently being evaluated and may have the potential to overcome T790M-mediated resistance by virtue of their irreversible inhibition of the receptor TK domain.
doi:10.1038/onc.2009.198
PMCID: PMC2849651  PMID: 19680293
epidermal growth factor receptor; mutation; non-small-cell lung cancer; tyrosine kinase inhibitor; tyrosine kinase
9.  Epidermal growth factor receptor regulates MET levels and invasiveness through hypoxia-inducible factor-1α in non-small cell lung cancer cells 
Oncogene  2010;29(18):2616-2627.
Recent studies have established that amplification of the MET proto-oncogene can cause resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) cell lines with EGFR-activating mutations. The role of non-amplified MET in EGFR-dependent signaling before TKI resistance, however, is not well understood. Using NSCLC cell lines and transgenic models, we demonstrate here that EGFR activation by either mutation or ligand binding increases MET gene expression and protein levels. Our analysis of 202 NSCLC patient specimens was consistent with these observations: levels of MET were significantly higher in NSCLC with EGFR mutations than in NSCLC with wild-type EGFR. EGFR regulation of MET levels in cell lines occurred through the hypoxia-inducible factor (HIF)-1α pathway in a hypoxia-independent manner. This regulation was lost, however, after MET gene amplification or overexpression of a constitutively active form of HIF-1α. EGFR- and hypoxia-induced invasiveness of NSCLC cells, but not cell survival, were found to be MET dependent. These findings establish that, absent MET amplification, EGFR signaling can regulate MET levels through HIF-1α and that MET is a key downstream mediator of EGFR-induced invasiveness in EGFR-dependent NSCLC cells.
doi:10.1038/onc.2010.16
PMCID: PMC3378055  PMID: 20154724
EGFR; MET; non-small cell lung cancer; HIF-1α; invasiveness
10.  Elevated BCRP/ABCG2 Expression Confers Acquired Resistance to Gefitinib in Wild-Type EGFR-Expressing Cells 
PLoS ONE  2011;6(6):e21428.
Background
The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive.
Methodology/Principal Findings
Here, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib.
Conclusions/Significance
Thus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR.
doi:10.1371/journal.pone.0021428
PMCID: PMC3121773  PMID: 21731744
11.  Clinical Validation of a PCR Assay for the Detection of EGFR Mutations in Non–Small-Cell Lung Cancer: Retrospective Testing of Specimens from the EURTAC Trial 
PLoS ONE  2014;9(2):e89518.
The EURTAC trial demonstrated that the tyrosine kinase inhibitor (TKI) erlotinib was superior to chemotherapy as first-line therapy for advanced non-small cell lung cancers (NSCLC) that harbor EGFR activating mutations in a predominantly Caucasian population. Based on EURTAC and several Asian trials, anti-EGFR TKIs are standard of care for EGFR mutation-positive NSCLC. We sought to validate a rapid multiplex EGFR mutation assay as a companion diagnostic assay to select patients for this therapy. Samples from the EURTAC trial were prospectively screened for EGFR mutations using a combination of laboratory-developed tests (LDTs), and tested retrospectively with the cobas EGFR mutation test (EGFR PCR test). The EGFR PCR test results were compared to the original LDT results and to Sanger sequencing, using a subset of specimens from patients screened for the trial. Residual tissue was available from 487 (47%) of the 1044 patients screened for the trial. The EGFR PCR test showed high concordance with LDT results with a 96.3% overall agreement. The clinical outcome of patients who were EGFR-mutation detected by the EGFR PCR test was very similar to the entire EURTAC cohort. The concordance between the EGFR PCR test and Sanger sequencing was 90.6%. In 78.9% of the discordant samples, the EGFR PCR test result was confirmed by a sensitive deep sequencing assay. This retrospective study demonstrates the clinical utility of the EGFR PCR test in the accurate selection of patients for anti-EGFR TKI therapy. The EGFR PCR test demonstrated improved performance relative to Sanger sequencing.
doi:10.1371/journal.pone.0089518
PMCID: PMC3934888  PMID: 24586842
12.  BRIEF REPORT: Compound EGFR mutations and response to EGFR tyrosine kinase inhibitors 
INTRODUCTION
Non-small-cell lung cancers (NSCLCs) containing epidermal growth factor receptor (EGFR) mutations are exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs). This is the case of the most common EGFR mutations affecting exon 18 (G719X), 19 (inframe deletions) and 21 (L858R and L861Q). However, the frequency of compound (i.e., double or complex) EGFR mutations - where an EGFR TKI sensitizing or other mutation is identified together with a mutation of unknown clinical significance – and their pattern of response/resistance to EGFR TKIs are less well described.
METHODS
We analyzed the EGFR mutation pattern of 79 cases of NSCLC harboring EGFR mutations, and compiled the genotype-response data for patients with NSCLCs with compound EGFR mutations treated with EGFR TKIs.
RESULTS
Out of the 79 EGFR mutated tumors identified, 11 (14%) had compound mutations. Most involved the EGFR TKI-sensitizing G719X (n=3, plus S768I or E709A), L858R (n=4, plus L747V, R776H, T790M or A871G), L861Q (n=1, plus E709V) and delL747_T751 (n=1, plus R776H). 8 patients received an EGFR TKI: 3 cases with G719X plus another mutation had partial responses (PR) to erlotinib; out of 3 cases with L858R plus another mutation, 2 displayed PRs and 1 (with EGFR-L858R+A871G) progressive disease to erlotinib; 1 NSCLC with EGFR-L861Q+E709A and 1 with delL747_T51+R776S had PRs to EGFR TKIs.
CONCLUSIONS
Compound EGFR mutations comprised 14% of all mutations identified during routine sequencing of exons 18–21 of EGFR in our cohort. Most patients with an EGFR TKI sensitizing mutation (G719X, exon 19 deletion, L858R and L861Q) in addition to an atypical mutation responded to EGFR TKIs. Reporting of the genotype-response pattern of NSCLCs with EGFR compound and other rare mutations, and the addition of this information to searchable databases will be helpful to select the appropriate therapy for EGFR mutated NSCLC.
doi:10.1097/JTO.0b013e3182781e35
PMCID: PMC3531043  PMID: 23242437
lung cancer; non-small-cell lung cancer; EGFR; EGFR mutation; erlotinib; gefitinib; tyrosine kinase inhibitor; L858R; L861Q; G719X; exon 19 deletion: compound; double; complex
13.  Activity of EGFR-tyrosine kinase and ALK inhibitors for EML4–ALK-rearranged non–small–cell lung cancer harbored coexisting EGFR mutation 
BMC Cancer  2013;13:262.
Background
The EML4–ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion oncogene represents a novel molecular target in a small subset of non–small–cell lung cancers (NSCLCs). The EML4–ALK fusion gene occurs generally in NSCLC without mutations in epidermal growth factor receptor (EGFR) and KRAS.
Case presentation
We report that a case of EML4–ALK-positive NSCLC with EGFR mutation had a response of stable disease to both an EGFR tyrosine kinase inhibitor (EGFR-TKI) and ALK inhibitor.
Conclusions
We described the first clinical report of a patient with EML4–ALK-positive NSCLC with EGFR mutation that had a response of stable disease to both single-agent EGFR-TKI and ALK inhibitor. EML4–ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4–ALK-positive NSCLC.
doi:10.1186/1471-2407-13-262
PMCID: PMC3671182  PMID: 23714228
EML4–ALK; EGFR mutation; Lung cancer
14.  Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab 
BMC Medicine  2012;10:28.
Background
The epidermal growth factor receptor (EGFR) is a validated therapeutic target in non-small cell lung cancer (NSCLC). However, current single agent receptor targeting does not achieve a maximal therapeutic effect, and some mutations confer resistance to current available agents. In the current study we have examined, in different NSCLC cell lines, the combined effect of RNA interference targeting the EGFR mRNA, and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors (TKIs) or a monoclonal antibody cetuximab.
Methods
NSCLC cells (cell lines HCC827, H292, H358, H1650, and H1975) were transfected with EGFR siRNA and/or treated with the TKIs gefitinib, erlotinib, and afatinib, and/or with the monoclonal antibody cetuximab. The reduction of EGFR mRNA expression was measured by real-time quantitative RT-PCR. The down-regulation of EGFR protein expression was measured by western blot, and the proliferation, viability, caspase3/7 activity, and apoptotic morphology were monitored by spectrophotometry, fluorimetry, and fluorescence microscopy. The combined effect of EGFR siRNA and different drugs was evaluated using a combination index.
Results
EGFR-specific siRNA strongly inhibited EGFR protein expression almost equally in all cell lines and inhibited cell growth and induced cell apoptosis in all NSCLC cell lines studied, albeit with a different magnitude. The effects on growth obtained with siRNA was strikingly different from the effects obtained with TKIs. The effects of siRNA probably correlate with the overall oncogenic significance of the receptor, which is only partly inhibited by the TKIs. The cells which showed weak response to TKIs, such as the H1975 cell line containing the T790M resistance mutation, were found to be responsive to siRNA knockdown of EGFR, as were cell lines with downstream TKI resistance mutations. The cell line HCC827, harboring an exon 19 deletion mutation, was more than 10-fold more sensitive to TKI proliferation inhibition and apoptosis induction than any of the other cell lines. Cetuximab alone had no relevant in vitro activity at concentrations obtainable in the clinic. The addition of EGFR siRNA to either TKIs or cetuximab additively enhanced growth inhibition and induction of apoptosis in all five cell lines, independent of the EGFR mutation status (wild-type or sensitizing mutation or resistant mutation). The strongest biological effect was observed when afatinib was combined with an EGFR-specific siRNA.
Conclusions
EGFR knockdown by siRNA further decreases the cell growth of lung cancer cells that are treated with TKIs or cetuximab alone, confirming that single agent drug targeting does not achieve a maximal biological effect. The siRNA inhibits EGFR oncogenic activity that bypasses downstream "resistance" mutations such as KRAS and PTEN. The combined treatment of siRNA and EGFR inhibitory agents is additive. The combination of a potent, irreversible kinase inhibitor such as afatinib, with EGFR-specific siRNAs should be further investigated as a new strategy in the treatment of lung cancer and other EGFR dependent cancers, including those with downstream resistance mutations.
doi:10.1186/1741-7015-10-28
PMCID: PMC3334713  PMID: 22436374
EGFR; RNA interference; tyrosine kinase inhibitors (TKIs); anti-EGFR monoclonal antibodies (mAbs); proliferation; apoptosis; lung cancer
15.  Comparison of KRAS and EGFR gene status between primary non-small cell lung cancer and local lymph node metastases: implications for clinical practice 
Background
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have been widely used for the treatment of non-small cell lung cancer (NSCLC). KRAS and EGFR somatic mutations in NSCLC may predict resistance and responsiveness to TKI, respectively. Nevertheless, most research to date has been conducted on samples from primary tumors. For many patients with advanced disease, their samples can only be obtained from metastases for test. The molecular characteristics of metastasized tumors may be different from those of primary tumors.
Materials and methods
Mutation status of KRAS and EGFR between primary tumors and local lymph node metastases of 80 Chinese patients with NSCLC were analyzed by direct sequencing. Five of them were given gefitinib as neoadjunvant treatment after the EGFR-TKI sensitive mutations were detected in their biopsies of mediastinal lymph nodes metastases. McNemar's test was used to compare the EGFR and KRAS mutation status between primary tumors and corresponding local lymph node metastases. Data evaluation was carried out with SPSS_13.0 statistical software.
Results
Among the 160 samples, one primary tumor and seven metastases were identified with KRAS mutations and 21 primary tumors and 26 metastases were found to have EGFR mutations. KRAS and EGFR mutation status was different between primary tumors and corresponding metastases in 6 (7.5%) and 7 (8.75%) patients, respectively. One patient with no TKI sensitive mutations detected in the primary tumor showed disease progression.
Conclusion
Our results suggest that a considerable proportion of NSCLC in Chinese population showed discrepancy in KRAS and EGFR mutation status between primary tumors and corresponding metastases. This observation may have important implication for the use of targeted TKI therapy in the treatment of NSCLC patients.
doi:10.1186/1756-9966-30-30
PMCID: PMC3069944  PMID: 21414214
16.  Alterations in EGFR and Related Genes following Neo-Adjuvant Chemotherapy in Chinese Patients with Non-Small Cell Lung Cancer 
PLoS ONE  2013;8(3):e51021.
Introduction
Genetic aberrancies within epidermal growth factor receptor (EGFR) pathway are associated with therapeutic outcomes of EGFR-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, the impact of chemotherapy on EGFR-related genes alterations has not been defined in NSCLC. Our study aims to investigate the impact of neoadjuvant chemotherapy (Neoadj-Chemo) on EGFR activating mutations and associated EGFR-TKIs resistance-related genes.
Patients and Methods
Matched tumor samples were obtained retrospectively from 66 NSCLC patients (stages IIb–IIIb) corresponding to pre- and post- Neoadj-Chemo. EGFR mutations were detected by denaturing high performance liquid chromatography (DHPLC) and confirmed by Amplification Refractory Mutation System technology (ARMS), KRAS mutations, T790M mutation and c-MET amplification were identified using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP), ARMS, and real-time PCR, respectively.
Results
Before Neoadj-Chemo, EGFR mutations were identified in 33.3% (22/66) of NSCLC patients. Only 18.2% (12/66) of patients carried EGFR mutations after Neoadj-Chemo (p = 0.013). The median peak value of EGFR 19 exon mutations decreased non-significantly after Neoadj-Chemo. KRAS mutation rate decreased from 4.6% (3/66) to 3.0% (2/66) with Neoadj-Chemo. Although the overall percentage of patients exhibiting c-MET amplifications (6.1% [4/66]) did not change with Neoadj-Chemo, two patients transitioned from negative to positive c-MET amplification, and two patients reversed these changes post-Neoadj-Chemo. T790M mutations were absent from all samples.
Conclusion
Neoadjuvant chemotherapy tends to decrease the mutation frequency of EGFR mutation and downstream genes, which suggests that real-time samples analysis for genetic aberrancies within EGFR pathways have important value to delineate specific patient populations and facilitate individualized treatment.
doi:10.1371/journal.pone.0051021
PMCID: PMC3592850  PMID: 23520442
17.  Sensitive methods for the detection of an insertion in exon 20 of the HER2 gene in the metastasis of non-small cell lung cancer to the central nervous system 
Oncology Letters  2013;6(4):1063-1067.
The HER2 (ErbB2/neu) protein is a member of the HER (ErbB) receptor family (EGFR, HER2, HER3 and HER4) that expresses tyrosine kinase activity in the intracellular domain. EGFR and HER2 overexpression is observed in numerous types of cancer, nevertheless, the susceptibility of patients with non-small cell lung cancer (NSCLC) to therapy with EGFR and HER2 tyrosine kinase inhibitors (TKIs) depends on mutations present in the respective coding genes (driver mutations). In the present study, PCR and amplified DNA fragment length analysis (FLA) were used along with the multi-temperature single-strand conformation polymorphism (MSSCP) technique in order to identify the 12 base pair insertion in exon 20 of the HER2 gene in 143 patients with NSCLC metastasis to the central nervous system. The prevalence of the HER2 gene mutation was correlated with mutations in the EGFR and BRAF genes. The insertion in exon 20 of the HER2 gene was observed in a single 77-year-old, non-smoking male, with poorly-differentiated adenocarcinoma of the lung (1.5% of adenocarcinoma patients). No other genetic abnormalities were identified in this patient. In the therapy of NSCLC patients with HER2 gene mutations, drugs that inhibit the EGFR and HER2 receptors, for example afatinib, may be effective. The identification of other driving mutations in NSCLC cells appears to be key to the appropriate qualification of molecular targeted therapies.
doi:10.3892/ol.2013.1495
PMCID: PMC3796408  PMID: 24137465
non-small cell lung cancer; metastasis to the central nervous system; HER2 mutation
18.  EGFR Polymorphism as a Predictor of Clinical Outcome in Advanced Lung Cancer Patients Treated with EGFR-TKI 
Yonsei Medical Journal  2012;53(6):1128-1135.
Purpose
Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of the efficacy of treatment with EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR gene were associated with clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with EGFR-TKI.
Materials and Methods
A polymorphic dinucleotide repeat in intron 1 [CA simple sequence repeat in intron 1(CA-SSR1)] in intron 1 and single nucleotide polymorphisms (SNP-216) in the promoter region of the EGFR gene were evaluated in 71 NSCLC patients by restriction fragment length polymorphism and DNA sequencing. The relationship between genetic polymorphisms and clinical outcomes of treatment with EGFR-TKIs was evaluated.
Results
SNP-216G/T polymorphisms were associated with the efficacy of EGFR-TKI. The response rate for the SNP-216G/T tended to be higher than that for G/G (62.5% vs. 27.4%, p=0.057). The SNP-216G/T genotype was also associated with longer progression-free survival compared with the GG genotype (16.7 months vs. 5.1 months, p=0.005). However, the length of CA-SSR1 was not associated with the efficacy of EGFR-TKI.
Conclusion
SNP-216G/T polymorphism was a potential predictor of clinical outcomes in NSCLC patients treated with EGFR-TKI.
doi:10.3349/ymj.2012.53.6.1128
PMCID: PMC3481391  PMID: 23074112
Polymorphism; lung cancer; EGFR tyrosine kinase inhibitor
19.  Curcumin Induces EGFR Degradation in Lung Adenocarcinoma and Modulates p38 Activation in Intestine: The Versatile Adjuvant for Gefitinib Therapy 
PLoS ONE  2011;6(8):e23756.
Background
Non-small cell lung cancer (NSCLC) patients with L858R or exon 19 deletion mutations in epidermal growth factor receptor (EGFR) have good responses to the tyrosine kinase inhibitor (TKI), gefitinib. However, patients with wild-type EGFR and acquired mutation in EGFR T790M are resistant to gefitinib treatment. Here, we showed that curcumin can improve the efficiency of gefitinib in the resistant NSCLC cells both in vitro and in vivo models.
Methods/Principal Findings
After screening 598 herbal and natural compounds, we found curcumin could inhibit cell proliferation in different gefitinib-resistant NSCLC cell lines; concentration-dependently down-regulate EGFR phosphorylation through promoting EGFR degradation in NSCLC cell lines with wild-type EGFR or T790M EGFR. In addition, the anti-tumor activity of gefitinib was potentiated via curcumin through blocking EGFR activation and inducing apoptosis in gefitinib-resistant NSCLC cell lines; also the combined treatment with curcumin and gefitinib exhibited significant inhibition in the CL1-5, A549 and H1975 xenografts tumor growth in SCID mice through reducing EGFR, c-MET, cyclin D1 expression, and inducing apoptosis activation through caspases-8, 9 and PARP. Interestingly, we observed that the combined treatment group represented better survival rate and less intestinal mucosal damage compare to gefitinib-alone therapy. We showed that curcumin attenuated the gefitinib-induced cell proliferation inhibition and apoptosis through altering p38 mitogen-activated protein kinase (MAPK) activation in intestinal epithelia cell.
Conclusions/Significance
Curcumin potentiates antitumor activity of gefitinib in cell lines and xenograft mice model of NSCLC through inhibition of proliferation, EGFR phosphorylation, and induction EGFR ubiquitination and apoptosis. In addition, curcumin attenuates gefitinib-induced gastrointestinal adverse effects via altering p38 activation. These findings provide a novel treatment strategy that curcumin as an adjuvant to increase the spectrum of the usage of gefitinib and overcome the gefitinib inefficiency in NSCLC patients.
doi:10.1371/journal.pone.0023756
PMCID: PMC3157465  PMID: 21858220
20.  The Fibroblast Growth Factor Receptor Signaling Pathway as a Mediator of Intrinsic Resistance to EGFR-specific Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer 
The EGFR has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) that have proven effective in a subset of non-small cell lung cancer (NSCLC) patients, many bearing gain-of-function EGFR mutations or egfr gene amplification. However, the majority (~80–90%) of NSCLC patients do not respond to EGFR-specific TKIs and a high rate of acquired resistance to these therapeutics is observed in those that do respond. Thus, EGFR-specific TKIs will not, as single agents, make a high impact on overall lung cancer survival. A number of studies support the activities of other receptor tyrosine kinase pathways including cMet, IGF-1R and FGFRs as mechanisms for both intrinsic and acquired resistance to EGFR TKIs. While the role of cMet and IGF-1R signaling systems as mechanisms of resistance to EGFR TKIs has been widely reviewed in recent years, the potential role of FGFR-dependent signaling as a mechanism for EGFR TKI resistance has more recently emerged and will be highlighted herein. Due to the high degree of homology of FGFRs with VEGFRs and PDGFRs, FGFR-active TKIs already exist via development of VEGFR-targeted TKIs as angiogenesis inhibitors. Thus, these agents could be rapidly advanced into clinical investigations as FGFR inhibitors, either alone or in combination with TKIs selective for EGFR, cMet or IGF-1R as a means to expand the spectrum of NSCLC patients that can be effectively targeted with TKI-directed therapies.
doi:10.1016/j.drup.2009.05.001
PMCID: PMC2763047  PMID: 19501013
FGF; FGFR; NSCLC; intrinsic resistance; receptor tyrosine kinase; tyrosine kinase inhibitors
21.  Cotargeting EGFR and autophagy signaling: A novel therapeutic strategy for non-small-cell lung cancer 
Epidermal growth factor receptor (EGFR) somatic mutations are found in the majority of non-small-cell lung cancers (NSCLCs) and patients with NSCLC who harbor EGFR mutations have been shown to exhibit increased sensitivity to the small-molecule EGFR-tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, the majority of tumors develop acquired resistance to EGFR-TKIs after a median of 10–16 months, which limits the clinical efficacy of these drugs. Autophagy, an important homeostatic cellular recycling mechanism, has emerged as a potential target for the acquired resistance phenotype. Recently, several studies demonstrated that autophagy may be induced in a dose-dependent manner by treatment of multiple cancer cell lines with EGFR-TKIs in vitro. Furthermore, it was recently reported that autophagy, as a cytoprotective response, may be activated by EGFR-TKIs in lung cancer cells and that the inhibition of autophagy enhanced the cytotoxic effect of EGFR-TKIs. In this review, we aimed to focus on the association between resistance to EGFR-TKIs and autophagy, and assess whether autophagy inhibition represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of NSCLC patients.
doi:10.3892/mco.2013.187
PMCID: PMC3915646  PMID: 24649300
epidermal growth factor receptor; autophagy; non-small-cell lung cancer; resistance
22.  Synergistic interaction between sorafenib and gemcitabine in EGFR-TKI-sensitive and EGFR-TKI-resistant human lung cancer cell lines 
Oncology Letters  2012;5(2):440-446.
Sorafenib is a highly selective multi-targeted agent and has been reported to have potent antitumor effects against various tumors, including human non-small cell lung cancer (NSCLC). In the present study, we explored the antitumor effect and associated molecular mechanisms of sorafenib against human lung cancer cell lines in vitro. We also investigated the efficacy of concurrent and sequential administration of sorafenib and gemcitabine in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-sensitive and EGFR-TKI-resistant NSCLC cell lines. The PC-9 (EGFR-TKI-sensitive, EGFR-mutated) and A549 (EGFR-TKI-resistant, K-Ras-mutated) NSCLC cell lines were treated with sorafenib and gemcitabine, alone, in combination or with different schedules. Cytotoxicity was assessed by MTT assay, cell cycle distribution was analyzed by flow cytometry and alterations in signaling pathways were analyzed by western blotting. We found that sorafenib exhibited dose-dependent growth inhibition in the EGFR-TKI-sensitive and EGFR-TKI-resistant NSCLC cell lines, and the sequence gemcitabine→sorafenib exhibited the strongest synergism. Sorafenib arrested the cell cycle at G1 phase, whereas gemcitabine caused arrest at S phase. The molecular mechanism of this synergism is that the downstream signaling pathways that were initially activated by gemcitabine exposure were efficiently suppressed by the subsequent exposure to sorafenib. By contrast, the reverse of this sequential administration resulted in antagonism, which may be due to differential effects on cell cycle arrest. The results suggest that sorafenib as a single agent exhibits anti-proliferative effects in vitro in NSCLC cell lines with EGFR and K-Ras mutations and that the sequential administration of gemcitabine followed by sorafenib is superior to sorafenib followed by gemcitabine and concurrent administration.
doi:10.3892/ol.2012.1017
PMCID: PMC3573056  PMID: 23420122
sorafenib; gemcitabine; non-small cell lung cancer; sequence treatment
23.  Oncogenic KRAS-induced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer 
The CXC chemokine interleukin-8 (IL-8) is an angiogenic growth factor that is overexpressed in various cancers, including non-small cell lung cancer (NSCLC). Previously, IL-8 was shown as a transcriptional target of RAS signaling, raising the possibility of its role in oncogenic KRAS-driven NSCLC. Using microarray analysis, we identified IL-8 as the most downregulated gene by shRNA-mediated KRAS knockdown in NCI-H1792 NSCLC cells where IL-8 is overexpressed. NSCLC cell lines harboring KRAS or EGFR mutations overexpressed IL-8, while IL-8 levels were more prominent in KRAS mutants compared to EGFR mutants. IL-8 expression was downregulated by shRNA-mediated KRAS knockdown in KRAS mutants or by treatment with EGFR tyrosine kinase inhibitors and EGFR siRNAs in EGFR mutants. In our analysis of the relationship of IL-8 expression with clinical parameters and mutation status of KRAS or EGFR in 89 NSCLC surgical specimens, IL-8 expression was shown to be significantly higher in NSCLCs of males, smokers, and elderly patients and those with pleural involvement and KRAS mutated adenocarcinomas. In KRAS mutant cells, the MEK inhibitor markedly decreased IL-8 expression, while the p38 inhibitor increased IL-8 expression. Attenuation of IL-8 function by siRNAs or a neutralizing antibody inhibited cell proliferation and migration of KRAS mutant/IL-8 overexpressing NSCLC cells. These results indicate that activating mutations of KRAS or EGFR upregulate IL-8 expression in NSCLC; IL-8 is highly expressed in NSCLCs from males, smokers, elderly patients, NSCLCs with pleural involvement, and KRAS-mutated adenocarcinomas; and IL-8 plays a role in cell growth and migration in oncogenic KRAS-driven NSCLC.
doi:10.1002/ijc.26164
PMCID: PMC3374723  PMID: 21544811
non-small cell lung cancer; KRAS; interleukin-8; molecular target
24.  A case of lung adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene 
BMC Cancer  2012;12:558.
Background
Lung cancer is the leading cause of cancer-related death worldwide. Epidermal growth factor receptor (EGFR) - tyrosine kinase inhibitor (TKI) is used for the patients with EGFR-mutant lung cancer. Recently, phase III studies in the patients with EGFR-mutant demonstrated that EGFR-TKI monotherapy improved progression-free survival compared with platinum-doublet chemotherapy. The echinoderm microtubule-associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion oncogene represents one of the newest molecular targets in non-small cell lung cancer (NSCLC). Patients who harbor EML4-ALK fusions have been associated with a lack of EGFR or KRAS mutations.
Case presentation
We report a 39-year-old patient diagnosed as adenocarcinoma harboring EGFR mutation and EML4-ALK fusion gene. We treated this patient with erlotinib as the third line therapy, but no clinical benefit was obtained.
Conclusion
We experienced a rare case with EGFR mutation and EML4-ALK. Any clinical benefit using EGFR-TKI was not obtained in our case. The therapeutic choice for the patients with more than one driver mutations is unclear. We needs further understanding of the lung cancer molecular biology and the biomarker infomation.
doi:10.1186/1471-2407-12-558
PMCID: PMC3515412  PMID: 23181703
Lung cancer; EGFR mutation; EML4-ALK; Erlotinib
25.  Treatment of Non Small Cell Lung Cancer: Overcoming the resistance to EGFR inhibitors 
Current Opinion in Oncology  2012;24(2):123-129.
PURPOSE OF REVIEW
Testing for epidermal growth factor receptor (EGFR) mutations has become standard practice in treating patients with advanced nonsmall cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are being offered as first line therapy in patients with EGFR activating mutations. These drugs offer an increased progression free survival and response rate compared to standard chemotherapy in this setting, however resistance invariably occurs. This review discusses the development of resistance to EGFR TKIs and the progress that is being made to better understand how to overcome this resistance.
RECENT FINDINGS
Results from recently published papers dealing with resistance to EGFR TKIs are allowing for a better understanding of this mechanism. No one treatment allows for overcoming this resistance. Understanding this resistance will likely become an individualized patient/tumor approach. Selecting which drug or drugs that may be suitable can only be determined based on the molecular mechanism of resistance.
SUMMARY
Progress is being made in our understanding of the multiple pathways of resistance. Using a tumors molecular signature at the time of progression can determine the best treatment option.
doi:10.1097/CCO.0b013e32834ec6a7
PMCID: PMC3277209  PMID: 22314615
Epidermal Growth Factor Receptor; Tyrosine Kinase Inhibitors; Resistance; Lung Cancer

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