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author:("Li, chunpoong")
1.  Magnetic resonance imaging in interventional therapy of patients with acute myocardial infarction prior to and after treatment 
The aim of the study was to investigate the cardiac magnetic resonance (CMR) imaging in interventional therapy of patients with acute myocardial infarction prior to and after treatment. Fifty-six cases of AMI patients with elective treatment by percutaneous coronary intervention (PCI) were continuously selected. Patients with an incidence of 7–10 days were treated with CMR and echocardiography to evaluate the quality of myocardial infarction, visual score method (VSM), wall motion score abnormality, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and left ventricular ejection fraction (LVEF). Patients with an incidence of 10–14 days were treated with PCI, and CMR and echocardiography were evaluated after 6 months, after which the occurrence of major adverse cardiac events (MACE) were compared. The infarction quality, VSM score and wall motion abnormality (WMA) score were significantly reduced following surgery, and the difference was statistically significant (P<0.05). Ultrasound evaluation of LVEDD, LVESD, and LVEF prior to and after surgery was compared, and the difference was not statistically significant (P>0.05). Evaluation of the magnetic resonance imaging (MRI) in LVEDD prior to surgery was increased compared with that of the ultrasound in LVEDD, whereas MRI in LVESD and LVEF was decreased compared to that of the ultrasound obtained for LVESD and LVEF. Additionally, postoperative LVEDD was reduced compared with preoperative LVEDD, whereas LVEF was increased, and the difference was statistically significant (P<0.05). However, the evaluation of LVESD using the two methods exhibited no significant change. MACE occurred in 7 (12.5%) of 56 cases. The infarction quality of patients in the MACE group following surgery indicated that VSM and WMA scores were significantly higher than the group without MACE, while LVEF was lower than the MACE group following surgery, and the difference was statistically significant (P<0.05), albeit the ultrasound results of LVEF indicated no difference. In conclusion, CMR evaluation of AMI patients with elective PCI treatment in myocardial remodeling and cardiac function were more sensitive and accurate than with cardiac ultrasound.
doi:10.3892/etm.2016.3537
PMCID: PMC4998127  PMID: 27588093
cardiac magnetic resonance imaging; acute myocardial infarction; interventional therapy; ultrasonic echocardiography; myocardial infarction quality; visual scoring method; wall motion abnormality score
2.  The Fd-GOGAT1 mutant gene lc7 confers resistance to Xanthomonas oryzae pv. Oryzae in rice 
Scientific Reports  2016;6:26411.
Disease resistance is an important goal of crop improvement. The molecular mechanism of resistance requires further study. Here, we report the identification of a rice leaf color mutant, lc7, which is defective in chlorophyll synthesis and photosynthesis but confers resistance to Xanthomonas oryzae pv. Oryzae (Xoo). Map-based cloning revealed that lc7 encodes a mutant ferredoxin-dependent glutamate synthase1 (Fd-GOGAT1). Fd-GOGAT1 has been proposed to have great potential for improving nitrogen-use efficiency, but its function in bacterial resistance has not been reported. The lc7 mutant accumulates excessive levels of ROS (reactive oxygen species) in the leaves, causing the leaf color to become yellow after the four-leaf stage. Compared to the wild type, lc7 mutants have a broad-spectrum high resistance to seven Xoo strains. Differentially expressed genes (DEGs) and qRT-PCR analysis indicate that many defense pathways that are involved in this broad-spectrum resistance are activated in the lc7 mutant. These results suggest that Fd-GOGAT1 plays an important role in broad-spectrum bacterial blight resistance, in addition to modulating nitrogen assimilation and chloroplast development.
doi:10.1038/srep26411
PMCID: PMC4876388  PMID: 27211925
3.  Distinct Clinical Characteristics of Pediatric Guillain-Barré Syndrome: A Comparative Study between Children and Adults in Northeast China 
PLoS ONE  2016;11(3):e0151611.
Objective
Clinical characteristics of pediatric Guillain-Barré syndrome (GBS) have been extensively studied whereas scarcely been compared with those of adult GBS. Herein we compared the clinical features of GBS between pediatric and adult patients.
Methods
We retrospectively collected the clinical data of 750 patients with GBS (541 adults and 209 children), and compared the clinical characteristics between children and adults.
Results
Pain was a more frequent complaint in children (17.2% vs 9.6%, p < 0.01), who were also found with shorter interval from disease onset to nadir (6.3d vs 7.3d, p < 0.01) and higher incidence of bulbar dysfunction (22.0% vs 14.8%, p < 0.05). The disease severity in children was comparable with adults. In addition, a higher incidence of pediatric GBS was found in summer, especially in July and August (both p < 0.01). However, the incidence of antecedent infections of different seasons in adult and pediatric patients was comparable (p > 0.05). The clinical features of acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) in children were overall comparable with adult ones (p > 0.05). Similar to adults, bulbar dysfunction (odds ratio [OR]: 4.621, 95% confidence interval [CI]: 1.240–17.218, p < 0.05) and lower nadir Medical Research Council (MRC) sum score (OR: 0.897, 95% CI: 0.855–0.941, p < 0.01) were also risk factors for mechanical ventilation in children. However, distinct from adult ones, autonomic dysfunction was significantly higher in mechanically ventilated childhood GBS (39.1% vs 8.8%, p < 0.01), which also served as a predictor for mechanical ventilation in pediatric GBS (OR: 70.415, 95% CI: 9.265–535.158, p < 0.01). As to the efficacy of intravenous immunoglobulin, insignificant difference was identified between children and adults.
Conclusion
The clinical features of pediatric GBS differ from those of adults. Autonomic dysfunction is an independent risk factor for mechanical ventilation in pediatric patients.
doi:10.1371/journal.pone.0151611
PMCID: PMC4790924  PMID: 26974666
4.  Incidence of Co-Infections of HIV, Herpes Simplex Virus Type 2 and Syphilis in a Large Cohort of Men Who Have Sex with Men in Beijing, China 
PLoS ONE  2016;11(1):e0147422.
Background
The HIV-epidemic among MSM in China has worsened. In this key population, prevalence of HSV-2 and syphilis infection and co-infection with HIV is high.
Methods
A longitudinal study was conducted (n = 962) in Beijing, China, with three overlapping cohorts (n = 857, 757 and 760) consisting of MSM that were free from pairs of infections of concern (i.e. HIV-HSV-2, HIV-syphilis, HSV-2-syphilis) at baseline to estimate incidence of HIV, HSV-2, syphilis, and those of co-infection.
Results
The incidence of HIV, HSV-2 and syphilis in the overall cohort was 3.90 (95% CI = 2.37, 5.43), 7.87 (95% CI = 5.74, 10.00) and 6.06 (95% CI = 4.18, 7.94) cases per 100 person-years (PYs), respectively. The incidence of HIV-HSV-2, HIV-Syphilis and HSV-2-Syphilis co-infections was 0.30 (95% CI = 0.29, 0.88), 1.02 (95% CI = 0.13, 2.17) and 1.41 (95% CI: 0.04, 2.78) cases per 100 PYs, respectively, in the three sub-cohorts constructed for this study.
Conclusions
The incidence of HIV, HSV-2 and syphilis was very high and those of their co-infections were relatively high. Such co-infections have negative impacts on the HIV/STI epidemics. Prevention practices need to take such co-infections into account.
doi:10.1371/journal.pone.0147422
PMCID: PMC4731205  PMID: 26820145
5.  Short-Term Prognosis of Mechanically Ventilated Patients With Guillain–Barré Syndrome Is Worsened by Corticosteroids as an Add-On Therapy 
Medicine  2015;94(43):e1898.
Abstract
Intravenous immunoglobulin (IVIg) has been proven most effective in treating Guillain–Barré syndrome (GBS). Corticosteroids as an add-on therapy have been prescribed in severe GBS cases. However, the efficacy of intravenous corticosteroids combined with IVIg in dealing with severe GBS remains unclear. We explored the therapeutic effects of different therapeutic regimens on the short-term prognosis of GBS patients, especially the severe cases.
We retrospectively analyzed the clinical data of 527 adult patients with GBS who were prescribed to different treatments from 2003 to 2014. The therapeutic effect of a treatment was evaluated by the improvement of Hughes Functional Grading Scale (HFGS) and Medical Research Council (MRC) sum score.
With comparable incidence of infectious complications (P > 0.05), more mechanically ventilated patients were found improvement after IVIg treatment than combination IVIg with intravenous corticosteroids (MRC: 97% vs. 72.4%, P < 0.05; HFGS: 97% vs. 72.4%, P < 0.05). As to bedridden patients without mechanical ventilation, incidence of infectious complications (P > 0.05) and ratio of patients who were improved after IVIg were insignificantly different from the combination therapy (MRC: 89.6% vs. 86.5%; HFGS: 69.6% vs. 61.5%; both P > 0.05), even if the intravenous corticosteroids were initiated within 7 days after onset (P > 0.05). In addition, supportive treatment was sufficient for patients who were able to walk with help (HFGS = 3) and mildly affected (HFGS < 3) when compared with IVIg and intravenous corticosteroids.
IVIg is sufficient to GBS patients who are unable to walk (HFGS > 3), while corticosteroids are detrimental for short-term prognosis in mechanically ventilated patients when used in combination with IVIg. Further prospective and randomized studies are warranted to validate this finding.
doi:10.1097/MD.0000000000001898
PMCID: PMC4985423  PMID: 26512609
6.  Predictors for mechanical ventilation and short-term prognosis in patients with Guillain-Barré syndrome 
Critical Care  2015;19(1):310.
Introduction
Guillain-Barré syndrome (GBS) is an immune-mediated disorder of the peripheral nervous system. Respiratory failure requiring mechanical ventilation (MV) is a serious complication of GBS. Identification of modifiable risk factors for MV and poor short-term prognosis in mechanically ventilated patients with GBS may contribute to the individualized management and may help improve the outcome of the patients.
Methods
We retrospectively analyzed the clinical data of 541 patients who were diagnosed with GBS from 2003 to 2014. Independent predictors for MV and short-term prognosis in mechanically ventilated patients were identified via multivariate logistic regression analysis.
Results
The mean age was 41.6 years with a male predilection (61.2 %). Eighty patients (14.8 %) required MV. Multivariate analysis revealed that shorter interval from onset to admission (p < 0.05), facial nerve palsy (p < 0.01), glossopharyngeal and vagal nerve deficits (p < 0.01) and lower Medical Research Council (MRC) sum score at nadir (p < 0.01) were risk factors for MV; disease occurrence in summer (p < 0.01) was a protective factor. As to prognostic factors, absence of antecedent infections (p < 0.01) and lower MRC sum score at nadir (p < 0.01) were predictors of poor short-term prognosis in mechanically ventilated patients regardless of treatment modality. We further investigated the predictors of poor short-term prognosis in patients requiring MV with different nadir MRC sum scores. Combined use of intravenous corticosteroids with intravenous immunoglobulin (odds ratio 10.200, 95 % confidence interval 1.068–97.407, p < 0.05) was an independent predictor of poor short-term prognosis in mechanically ventilated patients with a nadir MRC sum score from 0 to 12 points, regardless of existence of antecedent infection.
Conclusions
Clinical predictors of MV and poor short-term prognosis in mechanically ventilated GBS patients were distinct. Add-on use of intravenous corticosteroids was a risk factor for poor short-term prognosis in mechanically ventilated patients with a nadir MRC sum score from 0 to 12 points.
doi:10.1186/s13054-015-1037-z
PMCID: PMC4557605  PMID: 26330143
7.  Prevalence and Associated Factors of Unprotected Anal Intercourse with Regular Male Sex Partners among HIV Negative Men Who Have Sex with Men in China: A Cross-Sectional Survey 
PLoS ONE  2015;10(3):e0119977.
The HIV prevalence and incidence among men who have sex with men (MSM) in China are high. Unprotected anal intercourse (UAI) with a regular male sex partner (RP), a significant predictor of HIV sero-conversion, was high yet under-emphasized among MSM having RP (MSMRP). The present cross-sectional survey interviewed 307 HIV negative MSMRP recruited through convenient sampling from multiple sources, including venue-based outreaching, online recruitment, and referrals made by peers, in Beijing and Chengdu, China. Among MSMRP, the prevalence of UAI with RP in the last three months was 52.4%. The results of the multivariate analysis showed that trust and intimacy within the relationship with RP and presence of clinical depression symptoms were positively associated with UAI with RP in the last three months. Other associated scalar factors derived from the Theory of Planned Behavior were related to perceptions on condom use, including positive attitudes toward condom use (a negative association), subjective norm of the perception that MSM do not usually use condoms during anal intercourse with RP (a positive association), perceived behavioral control over condom use with RP (a negative association), and behavioral intention to use condoms with RP in the coming three months (a negative association). It is seen that MSMRP were at high risk of HIV/STD transmission. The associated factors hence involved those related to perceptions about condom use, mental health, and interpersonal relationship. Future interventions should take these multi-dimensional factors into account. In particular, future research to test the efficacy of couple-based interventions that include mental health elements needs to be conducted, as trust and intimacy within the relationship were associated with UAI among MSMRP, and mental health problems may exist for both the MSMRP and their RP.
doi:10.1371/journal.pone.0119977
PMCID: PMC4376721  PMID: 25816292
8.  Sym004, a novel anti-EGFR antibody mixture augments radiation response in human lung and head and neck cancers 
Molecular cancer therapeutics  2013;12(12):2772-2781.
Sym004 represents a novel EGFR targeting approach comprised of a mixture of two anti-EGFR antibodies directed against distinct epitopes of EGFR. In contrast to single anti-EGFR antibodies, Sym004 induces rapid and highly efficient degradation of EGFR. In the current study, we examine the capacity of Sym004 to augment radiation response in lung cancer and head and neck (H&N) cancer model systems. We first examined the anti-proliferative effect of Sym004 and confirmed 40∼60% growth inhibition by Sym004. Using clonogenic survival analysis, we identified that Sym004 potently increased cell kill by up to 10-fold following radiation exposure. A significant increase of γH2AX foci resulting from DNA double strand breaks was observed in Sym004-treated cells following exposure to radiation. Mechanistic studies further demonstrated that Sym004 enhanced radiation response via induction of cell cycle arrest followed by induction of apoptosis and cell death reflecting inhibitory effects on DNA damage repair. The expression of several critical molecules involved in radiation-induced DNA damage repair were significantly inhibited by Sym004, including DNAPK, NBS1, RAD50, and BRCA1. Using single and fractionated radiation in human tumor xenograft models, we confirmed that the combination of Sym004 and radiation resulted in significant tumor regrowth delay and superior anti-tumor effects compared to treatment with Sym004 or radiation alone. Taken together, these data reveal the strong capacity of Sym004 to augment radiation response in lung and H&N cancers. The unique action mechanism of Sym004 warrants further investigation as a promising EGFR targeting agent combined with radiotherapy in cancer therapy.
doi:10.1158/1535-7163.MCT-13-0587
PMCID: PMC3960925  PMID: 24130052
Sym004; EGFR; Antibody; Radiation; Repair
9.  Human Epidermal Growth Factor Receptor 3 (HER3) Blockade with U3-1287/AMG888 Enhances the Efficacy of Radiation Therapy in Lung and Head and Neck Carcinoma 
Discovery medicine  2013;16(87):79-92.
HER3 is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. In the present study, we investigated the capacity of the HER3 blocking antibody, U3-1287/AMG888, to modulate the in vitro and in vivo radiation response of human squamous cell carcinomas of the lung and head and neck. We screened a battery of cell lines from these tumors for HER3 expression and demonstrated that all cell lines screened exhibited expression of HER3. Importantly, U3-1287/AMG888 treatment could block both basal HER3 activity and radiation induced HER3 activation. Proliferation assays indicated that HER3 blockade could decrease the proliferation of both HNSCC cell line SCC6 and NSCLC cell line H226. Further, we demonstrated that U3-1287/AMG888 can sensitize cells to radiation in clonogenic survival assays, in addition to increasing DNA damage as detected via λ-H2AX immunofluo-rescence. To determine if U3-1287/AMG888 could enhance radiation sensitivity in vivo we performed tumor growth delay experiments using SCC6, SCC1483, and H226 xenografts. The results of these experiments indicated that the combination of U3-1287/AMG888 and radiation could decrease tumor growth in studies using single or fractionated doses of radiation. Analysis of HER3 expression in tumor samples indicated that radiation treatment activated HER3 in vivo and that U3-1287/AMG888 could abrogate this activation. Immunohistochemistry analysis of SCC6 tumors treated with both U3-1287/AMG888 and a single dose of radiation demonstrated that various cell survival and proliferation markers could be reduced. Collectively our findings suggest that U3-1287/AMG888 in combination with radiation has an impact on cell and tumor growth by increasing DNA damage and cell death. These findings suggest that HER3 may play an important role in response to radiation therapy and blocking its activity in combination with radiation may be of therapeutic benefit in human tumors.
PMCID: PMC3901945  PMID: 23998444
10.  Sym004, a Novel EGFR Antibody Mixture, Can Overcome Acquired Resistance to Cetuximab1 
Neoplasia (New York, N.Y.)  2013;15(10):1196-1206.
The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in a variety of human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for head and neck and colorectal cancer treatment, but many patients treated with cetuximab don't respond or eventually acquire resistance. To determine how tumor cells acquire resistance to cetuximab, we previously developed a model of acquired resistance using the non-small cell lung cancer line NCI-H226. These cetuximab-resistant (CtxR) cells exhibit increased steady-state EGFR expression secondary to alterations in EGFR trafficking and degradation and, further, retained dependence on EGFR signaling for enhanced growth potential. Here, we examined Sym004, a novel mixture of antibodies directed against distinct epitopes on the extracellular domain of EGFR, as an alternative therapy for CtxR tumor cells. Sym004 treatment of CtxR clones resulted in rapid EGFR degradation, followed by robust inhibition of cell proliferation and down-regulation of several mitogen-activated protein kinase pathways. To determine whether Sym004 could have therapeutic benefit in vivo, we established de novo CtxR NCI-H226 mouse xenografts and subsequently treated CtxR tumors with Sym004. Sym004 treatment of mice harboring CtxR tumors resulted in growth delay compared to mice continued on cetuximab. Levels of total and phospho-EGFR were robustly decreased in CtxR tumors treated with Sym004. Immunohistochemical analysis of these Sym004-treated xenograft tumors further demonstrated decreased expression of Ki67, and phospho-rpS6, as well as a modest increase in cleaved caspase-3. These results indicate that Sym004 may be an effective targeted therapy for CtxR tumors.
PMCID: PMC3819635  PMID: 24204198
11.  Yes and Lyn play a role in nuclear translocation of the Epidermal Growth Factor Receptor 
Oncogene  2012;32(6):759-767.
The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR antibody that has been approved for use in oncology. Previously we investigated mechanisms of resistance to cetuximab using a model derived from the non-small cell lung cancer line NCI-H226. We demonstrated that cetuximab-resistant clones (CtxR) had increased nuclear localization of the EGFR. This process was mediated by Src family kinases (SFK), and nuclear EGFR played a role in resistance to cetuximab. To better understand SFK mediated nuclear translocation of EGFR, we investigated which SFK member(s) controlled this process as well as the EGFR tyrosine residues that are involved. Analyses of mRNA and protein expression indicated up-regulation of the SFK members Yes and Lyn in all CtxR clones. Further, immunoprecipitation analysis revealed that EGFR interacts with Yes and Lyn in CtxR clones, but not in cetuximab-sensitive (CtxS) parental cells. Using RNAi interference, we found that knockdown of either Yes or Lyn led to loss of EGFR translocation to the nucleus. Conversely, overexpression of Yes or Lyn in low nuclear EGFR expressing CtxS parental cells led to increased nuclear EGFR. Chromatin immunoprecipitation (ChIP) assays confirmed nuclear EGFR complexes associated with the promoter of the known EGFR target genes B-Myb and iNOS. Further, all CtxR clones exhibited up-regulation of B-Myb and iNOS at the mRNA and protein levels. siRNAs directed at Yes or Lyn led to decreased binding of EGFR complexes to the B-Myb and iNOS promoters based on ChIP analyses. SFKs have been shown to phosphorylate EGFR on tyrosines 845 and 1101 (Y845 and Y1101) and mutation of Y1101, but not Y845, impaired nuclear entry of the EGFR. Taken together, our findings demonstrate that Yes and Lyn phosphorylate EGFR at Y1101 which influences EGFR nuclear translocation in this model of cetuximab resistance.
doi:10.1038/onc.2012.90
PMCID: PMC3381861  PMID: 22430206
nuclear EGFR; SFK; Yes; Lyn
12.  p53 modulates acquired resistance to EGFR inhibitors and radiation 
Cancer research  2011;71(22):7071-7079.
There is presently great interest in mechanisms of acquired resistance to EGFR inhibitors that are now being used widely in the treatment of a variety of common human cancers. To investigate these mechanisms we established EGFR inhibitor resistant clones from non-small cell lung cancer cells. A comparative analysis revealed that acquired resistance to EGFR inhibitors was associated consistently with the loss of p53 and cross-resistance to radiation. To examine the role of p53, we first knocked down p53 in sensitive parental cells and found a reduction in sensitivity to both EGFR inhibitors and radiation. Conversely, restoration of functional p53 in EGFR inhibitor resistant cells was sufficient to resensitize them to EGFR inhibitors or radiation in vitro and in vivo. Further studies indicate that p53 may enhance sensitivity to EGFR inhibitors and radiation via induction of cell cycle arrest, apoptosis and DNA damage repair. Taken together, these findings suggest a central role of p53 in the development of acquired resistance to EGFR inhibitors and prompt consideration to apply p53 restoration strategies in future clinical trials that combine EGFR inhibitors and radiation.
doi:10.1158/0008-5472.CAN-11-0128
PMCID: PMC3229180  PMID: 22068033
EGFR; Inhibitor; Radiation; Resistance; p53
13.  Erlotinib is a viable treatment for tumors with acquired resistance to cetuximab 
Cancer Biology & Therapy  2011;12(5):436-446.
The epidermal growth factor receptor (EGFR) is an ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab and cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical success; however, many tumors remain non-responsive or acquire resistance during therapy. To explore potential molecular mechanisms of acquired resistance to cetuximab we previously established a series of cetuximab-resistant clones by chronically exposing the NCI-H226 NSCLC cell line to escalating doses of cetuximab. Cetuximab-resistant clones exhibited a dramatic increase in the activation of EGFR, HER2 and HER3 receptors as well as increased signaling through the MAP K and AKT pathways. RNAi studies demonstrated dependence of cetuximab-resistant clones on the EGFR signaling network. These findings prompted investigation on whether or not cells with acquired resistance to cetuximab would be sensitive to the EGFR targeted TKI erlotinib. In vitro, erlotinib was able to decrease signaling through the EGFR axis, decrease cellular proliferation and induce apoptosis. To determine if erlotinib could have therapeutic benefit in vivo, we established cetuximab-resistant NCI-H226 mouse xenografts, and subsequently treated them with erlotinib. Mice harboring cetuximab-resistant tumors treated with erlotinib exhibited either a tumor regression or growth delay as compared with vehicle controls. Analysis of the erlotinib treated tumors demonstrated a decrease in cell proliferation and increased rates of apoptosis. The work presented herein suggests that (1) cells with acquired resistance to cetuximab maintain their dependence on EGFR and (2) tumors developing resistance to cetuximab can benefit from subsequent treatment with erlotinib, providing rationale for its use in the setting of cetuximab resistance.
doi:10.4161/cbt.12.5.16394
PMCID: PMC3219082  PMID: 21725209
EGFR; mABs; cetuximab resistance; TKI; erlotinib
14.  The Nuclear Epidermal Growth Factor Receptor Signaling Network and its Role in Cancer 
Discovery Medicine  2011;12(66):419-432.
The epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (RTKs). EGFR activation via ligand binding results in signaling through various pathways ultimately resulting in cellular proliferation, survival, angiogenesis, invasion, and metastasis. Aberrant expression or activity of EGFR has been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, pancreatic cancer and brain cancer. Thus intense efforts have been made to inhibit the activity of EGFR by designing antibodies against the ligand binding domains (cetuximab and panitumumab) or small molecules against the tyrosine kinase domains (erlotinib, gefitinib, and lapatinib). Although targeting membrane bound EGFR has shown benefit a new and emerging role for the EGFR is now being elucidated. In this review we will summarize the current knowledge of the nuclear EGFR signaling network, including how it is trafficked to the nucleus, the functions it serves in the nucleus, and how these functions impact cancer progression, survival and response to chemotherapeutics.
PMCID: PMC3305885  PMID: 22127113
nuclear EGFR; transcription factor; poor overall survival; resistance
15.  Dasatinib blocks cetuximab- and radiation-induced nuclear translocation of the epidermal growth factor receptor in head and neck squamous cell carcinoma 
Background and Purpose
The aberrant expression of epidermal growth factor receptor (EGFR) has been linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III trial combining cetuximab with radiation confirmed a strong survival advantage. However, both cetuximab and radiation can promote EGFR translocation to the nucleus where it enhances resistance to both of these modalities. In this report we sought to determine how to block cetuximab and radiation–induced translocation of EGFR to the nucleus in HNSCC cell lines.
Material and Methods
We utilized three established HNSCC cell lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of EGFR after treatment with cetuximab or radiation. We then utilized dasatinib (BMS-354825), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src Family Kinases, to determine if SFKs blockade could abrogate cetuximab and radiation-induced nuclear EGFR translocation.
Results
Cetuximab and radiation treatment of all three HNSCC lines lead to translocation of the EGFR to the nucleus. Blockade of SFKs abrogated cetuximab and radiation-induced EGFR translocation to the nucleus.
Conclusions
The data presented in this report suggests that both cetuximab and radiation can promote EGFR translocation to the nucleus and dasatinib can inhibit this process. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC.
doi:10.1016/j.radonc.2010.06.010
PMCID: PMC2974772  PMID: 20667610
EGFR; cetuximab; radiation; Src family kinases; dasatinib; head and neck cancer
16.  Dasatinib sensitizes KRAS mutant colorectal tumors to cetuximab 
Oncogene  2010;30(5):561-574.
KRAS mutation is a predictive biomarker for resistance to cetuximab (Erbitux®) in metastatic colorectal cancer (mCRC). This study sought to determine if KRAS mutant CRC lines could be sensitized to cetuximab using dasatinib (BMS-354825, sprycel®) a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src Family Kinases. We analyzed 16 CRC lines for: 1) KRAS mutation status, 2) dependence on mutant KRAS signaling, 3) expression level of EGFR and SFKs. From these analyses, we selected three KRAS mutant (LS180, LoVo, and HCT116) cell lines, and two KRAS wild type cell lines (SW48 and CaCo2). In vitro, using Poly-D-Lysine/laminin plates, KRAS mutant cell lines were resistant to cetuximab whereas parental controls showed sensitivity to cetuximab. Treatment with cetuximab and dasatinib showed a greater anti-proliferative effect on KRAS mutant line as compared to either agent alone both in vitro and in vivo. To investigate potential mechanisms for this anti-proliferative response in the combinatorial therapy we performed Human Phospho-kinase Antibody Array analysis measuring the relative phosphorylation levels of phosphorylation of 39 intracellular proteins in untreated, cetuximab, dasatinib or the combinatorial treatment in LS180, LoVo and HCT116 cells. The results of this experiment showed a decrease in a broad spectrum of kinases centered on the β-catenin pathway, the classical MAPK pathway, AKT/mTOR pathway and the family of STAT transcription factors when compared to the untreated control or monotherapy treatments. Next we analyzed tumor growth with cetuximab, dasatinib or the combination in vivo. KRAS mutant xenografts showed resistance to cetuximab therapy, whereas KRAS wild type demonstrated an anti-tumor response when treated with cetuximab. KRAS mutant tumors exhibited minimal response to dasatinib monotherapy. However, as in vitro, KRAS mutant lines exhibited a response to the combination of cetuximab and dasatinib. Combinatorial treatment of KRAS mutant xenografts resulted in decreased cell proliferation as measured by Ki67 and higher rates of apoptosis as measured by TUNEL. The data presented herein indicate that dasatinib can sensitize KRAS mutant CRC tumors to cetuximab and may do so by altering the activity of several key-signaling pathways. Further, these results suggest that signaling via the EGFR and SFKs may be necessary for cell proliferation and survival of KRAS mutant CRC tumors. This data strengthen the rationale for clinical trials in this genetic setting combining cetuximab and dasatinib.
doi:10.1038/onc.2010.430
PMCID: PMC3025039  PMID: 20956938
Cetuximab; resistance; KRAS mutation; dasatinib; EGFR; SRC; colorectal cancer
17.  Nuclear EGFR Contributes to Acquired Resistance to Cetuximab 
Oncogene  2009;28(43):3801-3813.
Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR blocking-antibody that has been approved for the treatment of patients with cancers of the head and neck (HNSCC) and metastatic colorectal cancer (mCRC). Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that cetuximab-resistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin (AR), heparin-binding EGF (HB-EGF) and β-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and re-sensitization to cetuximab. In addition, expression of a nuclear localization sequence tagged EGFR in cetuximab-sensitive cells increased resistance to cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with cetuximab-resistant tumors with inhibitors of SFKs in combination with cetuximab.
doi:10.1038/onc.2009.234
PMCID: PMC2900381  PMID: 19684613
EGFR; nuclear; cetuximab; resistance; Src-family kinases; dasatinib

Results 1-17 (17)