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1.  Exploiting the head and neck cancer oncogenome: Widespread PI3K-mTOR pathway alterations and novel molecular targets 
Cancer discovery  2013;3(7):722-725.
Two studies published in this issue of Cancer Discovery describe the emerging mutational landscape of head and neck squamous cell carcinomas (HNSCC) and their genomic and epigenetic alterations, thus identifying novel actionable cancer drivers and predictive biomarkers for targeted therapies. Most genomic alterations in HNSCC converge in a handful of molecular pathways resulting in cell cycle deregulation, genomic instability, cell differentiation defects, and persistent mitogenic signaling, the latter involving aberrant PI3K/mTOR pathway activation thereby rendering HNSCC responsive to PI3K/mTOR inhibitors.
PMCID: PMC4348071  PMID: 23847349
2.  Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199 
Cancer discovery  2014;4(9):1074-1087.
Acute Lymphoblastic Leukemia (ALL) is a hematopoietic malignancy derived from immature B-and T-lymphoid cells (T-ALL). In T-ALL there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we utilized mitochondrial BH3 profiling to determine anti-apoptotic dependencies in T-ALL. We found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer bears ETP phenotype, in which case it is BCL-2 dependent. These distinctions directly relate to differential sensitivity to the BH3 mimetics ABT-263 and ABT-199 both in vitro and in vivo. We thus describe for the first time a change of anti-apoptotic dependence that is related to the differentiation stage of the leukemic clone. Our findings demonstrate that BCL-2 is a clinically relevant target for therapeutic intervention with ABT-199 in ETP-ALL.
PMCID: PMC4154982  PMID: 24994123
BCL-2; BCL-XL; ABT-199; ABT-263; Acute Lymphoblastic Leukemia; T-cell ALL; ETP; B-cell ALL; BH3 profiling
3.  Cell Cycle Reprogramming for PI3K Inhibition Overrides Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma 
Cancer discovery  2014;4(9):1022-1035.
Despite the unprecedented clinical activity of the Bruton’s tyrosine kinase inhibitor ibrutinib in MCL, acquired-resistance is common. By longitudinal integrative whole-exome and whole-transcriptome sequencing and targeted sequencing, we identified the first relapse-specific C481S mutation at the ibrutinib-binding site of BTK in MCL cells at progression following a durable response. This mutation enhanced BTK and AKT activation and tissue-specific proliferation of resistant MCL cells driven by CDK4 activation. It was absent, however, in patients with primary-resistance or progression following transient response to ibrutinib, suggesting alternative mechanisms of resistance. Through synergistic induction of PIK3IP1 and inhibition of PI3K-AKT activation, prolonged early G1 arrest induced by PD 0332991 (palbociclib) inhibition of CDK4 sensitized resistant lymphoma cells to ibrutinib killing when BTK was unmutated, and to PI3K inhibitors independent of C481S mutation. These data identify a genomic basis for acquired-ibrutinib resistance in MCL and suggest a strategy to override both primary- and acquired-ibrutinib resistance.
PMCID: PMC4155003  PMID: 25082755
Ibrutinib; PD 0332991; AKT
4.  Synthetic lethality in ATM-deficient RAD50-mutant tumors underlie outlier response to cancer therapy 
Cancer discovery  2014;4(9):1014-1021.
Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small cell cancer to combined checkpoint kinase 1 (Chk1) inhibition and DNA damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of Chk1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy whereby checkpoint inhibition in combination with DNA damaging chemotherapy is synthetically lethal in tumor but not normal cells with somatic mutations that impair Mre11 complex function.
PMCID: PMC4155059  PMID: 24934408
DNA damage and repair; cancer genomics; exceptional responders; targeted and systemic therapy; RAD50
5.  Tracing the roots of cancer evolution 
Cancer discovery  2014;4(9):995-997.
By comparing the genomes of progenitor cells and mature cells of lymphoid and myeloid lineages in CLL patients, Damm and colleagues confirmed that CLL originates from pre-leukemic CD34+ progenitor cells and identified early CLL mutations that are associated with these progenitor cells. Moreover, they discovered that deregulation of BCR signaling may be one of the hallmarks of CLL, particularly in tumors with EGR2 mutations.
PMCID: PMC4155509  PMID: 25185189
6.  RADical response puts an exceptional responder in CHKmate: a synthetic lethal curative response to DNA-damaging chemotherapy? 
Cancer discovery  2014;4(9):988-990.
In this issue of Cancer Discovery, AI-Ahmadie and colleagues identify a somatic mutation in the Rad50 gene as a likely contributing factor to an unusual curative response to systemic combination therapy employing the DNA-damaging agent, irinotecan, and a checkpoint kinase 1(Chk1) inhibitor in a patient with recurrent, metastatic small-cell cancer. This study highlights the importance of in-depth analysis of exceptional responders to chemo and targeted therapy in early phase clinical trials and opens new avenues for developing cancer genome-based combination therapy to improve the efficacy of traditional chemotherapy through synthetically lethal interactions.
PMCID: PMC4155513  PMID: 25185187
7.  Patient Derived Xenograft Models: An Emerging Platform for Translational Cancer Research 
Cancer discovery  2014;4(9):998-1013.
Recently, there has been increasing interest in the development and characterization of patient derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histological and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biological studies, and personalized medicine strategies. This paper summarizes the current state of the art in this field including methodological issues, available collections, practical applications, challenges and shortcoming, and future directions, and introduces a European consortium of PDX models.
PMCID: PMC4167608  PMID: 25185190
PDX; Mouse Models; Preclinical Studies; Avatar; Xenopatient; Orthoxenografts; Tumorgraft
8.  AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer 
Cancer discovery  2014;4(9):1046-1061.
First generation EGF receptor tyrosine kinase inhibitors (EGFR TKIs) provide significant clinical benefit in patients with advanced EGFR mutant (EGFRm+) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent and selective third generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This monoanilino-pyrimidine compound is structurally distinct from other third generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Pre-clinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR mutant tumor xenograft and transgenic models. The treatment of two patients with advanced EGFRm T790M+ NSCLC is described as proof of principle.
PMCID: PMC4315625  PMID: 24893891
EGFR mutant lung cancer; AZD9291; EGFR tyrosine kinase inhibitor
9.  Hello out there… is anybody listening? 
Cancer discovery  2012;2(12):1084-1086.
PMCID: PMC4326255  PMID: 23230186
10.  [No title available] 
PMCID: PMC3946319  PMID: 24441285
11.  The Democratization of the Oncogene 
Cancer discovery  2014;4(8):870-872.
The identification of novel, oncogenic gene rearrangements in inflammatory myofibroblastic tumor (IMT) demonstrates the potential of next generation sequencing (NGS) platforms for the detection of therapeutically relevant oncogenes across multiple tumor types, but raises significant questions relating to the investigation of targeted therapies in this new era of widespread NGS testing.
PMCID: PMC4123669  PMID: 25092743
12.  Mouse models address key concerns regarding autophagy inhibition in cancer therapy 
Cancer discovery  2014;4(8):873-875.
With multiple clinical trials underway targeting autophagy against cancer, Yang et al. (1) and Karsli-Uzunbas et al. (2) address important concerns regarding autophagy inhibition in cancer patients using genetically engineered mouse models (GEMMs) that more accurately represent the tumor biology found in human pancreatic and lung cancer patients.
PMCID: PMC4124512  PMID: 25092744
13.  NSD3-NUT Fusion Oncoprotein in NUT Midline Carcinoma: Implications for a Novel Oncogenic Mechanism 
Cancer discovery  2014;4(8):928-941.
NUT midline carcinoma (NMC) is an aggressive subtype of squamous cell carcinoma that typically harbors BRD4/3-NUT fusion oncoproteins that block differentiation and maintain tumor growth. In 20% of cases NUT is fused to uncharacterized non-BRD gene(s). We established a new patient-derived NMC cell line (1221) and demonstrated that it harbors a novel NSD3-NUT fusion oncogene. We find that NSD3-NUT is both necessary and sufficient for the blockade of differentiation and maintenance of proliferation in NMC cells. NSD3-NUT binds to BRD4, and BRD bromodomain inhibitors induce differentiation and arrest proliferation of 1221 cells. We find further that NSD3 is required for the blockade of differentiation in BRD4-NUT-expressing NMCs. These findings identify NSD3 as a novel critical oncogenic component and potential therapeutic target in NMC.
PMCID: PMC4125436  PMID: 24875858
Cancer discovery  2014;4(8):942-955.
Loss of PTEN is a common event in many cancers and leads to hyperactivation of the PI 3-K/Akt signaling pathway. The mechanisms by which Akt isoforms mediate signaling to phenotypes associated with PTEN-inactivation in cancer have not been defined. Here we show that Akt2 is exclusively required for PTEN-deficient prostate tumor spheroid maintenance whereas Akt1 is dispensable. shRNA silencing of Akt2 but not Akt1 promotes regression of prostate cancer xenografts. Mechanistically, we show that Akt2 silencing up-regulates p21 and the pro-apoptotic protein Bax and downregulates the insulin-like growth factor receptor-1. We also show that p21 is an effector of Akt2 in mediating prostate tumor maintenance. Moreover, Akt2 is also exclusively required for the maintenance and survival of other PTEN-deficient solid tumors, including breast cancer and glioblastoma. These findings identify a specific function for Akt2 in mediating survival of PTEN-deficient tumors and provide a rationale for developing therapeutics targeting Akt2.
PMCID: PMC4125464  PMID: 24838891
15.  EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing 
Cancer discovery  2014;4(8):956-971.
Glioblastomas with EGFR amplification represent approximately 50% of newly diagnosed cases and recent studies have revealed frequent coexistence of multiple EGFR aberrations within the same tumor with implications for mutation cooperation and treatment resistance. However, bulk tumor sequencing studies cannot resolve the patterns of how the multiple EGFR aberrations coexist with other mutations within single tumor cells. Here we applied a population-based single-cell whole genome sequencing methodology to characterize genomic heterogeneity in EGFR amplified glioblastomas. Our analysis effectively identified clonal events, including a novel translocation of a super enhancer to the TERT promoter, as well as subclonal loss-of-heterozygosity and multiple EGFR mutational variants within tumors. Correlating the EGFR mutations onto the cellular hierarchy revealed that EGFR truncation variants (EGFRvII and EGFR Carboxyl-terminal deletions) identified in the bulk tumor segregate into non-overlapping subclonal populations. In vitro and in vivo functional studies show EGFRvII is oncogenic and sensitive to EGFR inhibitors currently in clinical trials. Thus the association between diverse activating mutations in EGFR and other subclonal mutations within a single tumor supports an intrinsic mechanism for proliferative and clonal diversification with broad implications in resistance to treatment.
PMCID: PMC4125473  PMID: 24893890
single-cell sequencing; single-nucleus sequencing; glioblastoma; EGFR; EGFR variant II
16.  Inflammatory Myofibroblastic Tumors harbor multiple potentially actionable kinase fusions 
Cancer discovery  2014;4(8):889-895.
Inflammatory myofibroblastic tumor (IMT) is a neoplasm which typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. While 50% of IMTs harbor ALK rearrangements, no therapeutic targets have been identified in ALK negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of an 8 year old boy with treatment-refractory ALK negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor, crizotinib. This case prompted assessment of a larger series of IMTs. Next generation sequencing revealed that 85% of cases evaluated harbored kinase fusions, involving ALK, ROS1, or PDGFRβ. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.
PMCID: PMC4125481  PMID: 24875859
Inflammatory myofibroblastic tumor; ALK; ROS1; PDGFRβ; tyrosine kinase; tyrosine kinase inhibitor; crizotinib; cancer; sarcoma; targeted therapeutics; next generation sequencing; gene rearrangement; gene fusion
17.  Vulnerabilities of PTEN-p53-deficient prostate cancers to compound PARP/PI3K inhibition 
Cancer discovery  2014;4(8):896-904.
Prostate cancer (CaP) is the most prevalent cancer in males and treatment options are limited for advanced forms of the disease. Loss of the PTEN and p53 tumor suppressor genes is commonly observed in CaP, while their compound loss is often observed in advanced CaP. Here we show, that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the pro-survival signalling PI3K-AKT pathway limits the efficacy of a PARP-single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human CaP cell lines and in a Pten/p53 deficient mouse model of advanced CaP. Our findings therefore identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient CaP.
PMCID: PMC4125493  PMID: 24866151
PTEN; Prostate; PARP; PI3K; Senescence
18.  Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations 
Cancer discovery  2014;4(8):905-913.
Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of p53, we demonstrate that while genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. Additionally, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Lastly, a mouse pre-clinical trial using cohorts of genetically characterized patient derived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together our data support the critical role of autophagy in pancreatic cancer and that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status.
PMCID: PMC4125497  PMID: 24875860
autophagy; pancreatic cancer; p53; chloroquine; metabolism; Atg5
19.  Autophagy is Required for Glucose Homeostasis and Lung Tumor Maintenance 
Cancer discovery  2014;4(8):914-927.
Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy-related-7, Atg7, throughout adult mice. Here we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2–3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non-small-cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with pre-existing NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This anti-tumor activity occurred prior to destruction of normal tissues, suggesting that, acute autophagy inhibition may be therapeutically beneficial in cancer.
PMCID: PMC4125614  PMID: 24875857
autophagy; fasting; hypoglycemia; cancer; oncocytoma
20.  Fingerprinting Acute Leukemia: DNA Methylation Profiling of B-Acute Lymphoblastic Leukemia 
Cancer discovery  2012;2(11):976-978.
In this issue of Cancer Discovery, Geng and colleagues report on their use of a combination of promoter cytosine methylation profiling with gene expression and ChIP sequencing to elucidate molecular signatures of adult B-acute lymphoblastic leukemia patient samples with BCR–ABL1, E2A–PBX1, and MLL rearrangements. The unique epigenetic and gene expression signatures of these clinically unfavorable B-ALL subtypes identify novel biomarkers and provide a strong rationale for repurposing existing therapies to treat these molecularly distinct diseases.
PMCID: PMC4307588  PMID: 23148371
21.  Lineage specific biomarkers predict response to FGFR inhibition 
Cancer discovery  2012;2(12):1081-1083.
In this issue of Cancer Discovery, Guagnano and colleagues utilise a large and diverse annotated collection of cancer cell lines, the “Cancer Cell Line Encyclopedia”, to correlate whole genome expression and genomic alteration datasets with cell line sensitivity data to the novel pan-FGFR inhibitor NVP-BGJ398. Their findings not only underscore the preclinical utility of such cell line panels in identifying predictive biomarkers, but also the emergence of the FGFRs as valid therapeutic targets, across an increasingly broad range of malignancies.
PMCID: PMC4300517  PMID: 23230185
22.  [No title available] 
PMCID: PMC4293454  PMID: 24436049
23.  Scanning for Clues to Better Use Selective Estrogen Receptor Modulators 
Cancer discovery  2013;3(7):728-729.
Ingle and colleagues present timely findings identifying genetic variants associated with response to selective estrogen receptor modulator therapy that when substantiated in follow-up may represent an important step towards understanding estrogen-dependent induction of BRCA1 expression and advancing individualized preventive medicine in women at high risk for developing breast cancer.
PMCID: PMC4285377  PMID: 23847351
24.  SPSB1 Promotes Breast Cancer Recurrence by Potentiating c-MET Signaling 
Cancer discovery  2014;4(7):790-803.
Breast cancer mortality is principally due to tumor recurrence; however, the molecular mechanisms underlying this process are poorly understood. We now demonstrate that the suppressor of cytokine signaling protein SPSB1 is spontaneously upregulated during mammary tumor recurrence and is both necessary and sufficient to promote tumor recurrence in genetically engineered mouse models. The recurrence-promoting effects of SPSB1 result from its ability to protect cells from apoptosis induced by HER2/neu pathway inhibition or chemotherapy. This, in turn, is attributable to SPSB1 potentiation of c-MET signaling, such that preexisting SPSB1-overexpressing tumor cells are selected for following HER2/neu downregulation. Consistent with this, SPSB1 expression is positively correlated with c-MET activity in human breast cancers and with an increased risk of relapse in patients with breast cancer in a manner that is dependent upon c-MET activity. Our findings define a novel pathway that contributes to breast cancer recurrence and provide the first evidence implicating SPSB proteins in cancer.
The principal cause of death from breast cancer is recurrence. This study identifies SPSB1 as a critical mediator of breast cancer recurrence, suggests activation of the SPSB1/c-MET pathway as an important mechanism of therapeutic resistance in breast cancers, and emphasizes that pharmacological targets for recurrence may be unique to this stage of tumor progression.
PMCID: PMC4121738  PMID: 24786206
SPSB1; c-MET; breast cancer; recurrence; apoptosis
25.  A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors 
Cancer discovery  2014;4(7):816-827.
Most melanomas harbor oncogenic BRAFV600 mutations, which constitutively activate the MAP kinase (MAPK) pathway. Although MAPK pathway inhibitors show clinical benefit in BRAFV600-mutant melanoma, it remains incompletely understood why 10-20% of patients fail to respond. Here, we show that RAF inhibitor sensitive and resistant BRAFV600-mutant melanomas display distinct transcriptional profiles. Whereas most drug-sensitive cell lines and patient biopsies showed high expression and activity of the melanocytic lineage transcription factor MITF, intrinsically resistant cell lines and biopsies displayed low MITF expression but higher levels of NF-κB signaling and the receptor tyrosine kinase AXL. In vitro, these MITF-low/NF-κB-high melanomas were resistant to inhibition of RAF and MEK, singly or in combination, and ERK. Moreover, in cell lines, NF-κB activation antagonized MITF expression and induced both resistance marker genes and drug resistance. Thus, distinct cell states characterized by MITF or NF-κB activity may influence intrinsic resistance to MAPK pathway inhibitors in BRAFV600-mutant melanoma.
PMCID: PMC4154497  PMID: 24771846
MITF; NF-κB; MAPK pathway; melanoma; intrinsic resistance

Results 1-25 (261)