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Genetic Modifiers of EGFR Dependence in Non-Small Cell Lung Cancer

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Genetic Modifiers of EGFR Dependence in Non-Small Cell Lung Cancer Genetic modifiers of EGFR dependence in non-small cell lung cancer Tanaz Sharifniaa,b,c, Victor Rusua,d, Federica Piccionia, Mukta Bagula, Marcin Imielinskia,b,c, Andrew D. Cherniacka, Chandra Sekhar Pedamallua,c, Bang Wonga, Frederick H. Wilsona,c, Levi A. Garrawaya,c, David Altshulera,d,e, Todd R. Goluba, David E. Roota, Aravind Subramaniana, and Matthew Meyersona,b,c,1 aBroad Institute of Harvard and MIT, Cambridge, MA 02142; Departments of bPathology and dGenetics and Medicine, Harvard Medical School, Boston, MA 02115; cDepartment of Medical Oncology, Dana–Farber Cancer Institute, Boston, MA 02115; and eDepartment of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114 Edited by Bert Vogelstein, Johns Hopkins University, Baltimore, MD, and approved November 18, 2014 (received for review June 29, 2014) Lung adenocarcinomas harboring activating mutations in the achieved via EGFR activation in MET-dependent cells (13), and epidermal growth factor receptor (EGFR) represent a common mo- analogous examples of reciprocal kinase switching have been lecular subset of non-small cell lung cancer (NSCLC) cases. EGFR reported in other kinase-driven cancer models (14, 15). These and mutations predict sensitivity to EGFR tyrosine kinase inhibitors other findings suggest that compensatory kinase switching may be (TKIs) and thus represent a dependency in NSCLCs harboring these a more general way in which oncogene-dependent cancers over- alterations, but the genetic basis of EGFR dependence is not fully come reliance on their primary driver kinase (14, 16), but the full- understood. Here, we applied an unbiased, ORF-based screen to range of kinases capable of mediating EGFR bypass has not been identify genetic modifiers of EGFR dependence in EGFR-mutant systematically studied. Recent advances in large-scale functional genetic libraries have NSCLC cells. This approach identified 18 kinase and kinase-related made it possible to query a wide range of genetic perturbations for genes whose overexpression can substitute for EGFR in EGFR- their ability to modulate specific cellular phenotypes in mammalian dependent PC9 cells, and these genes include seven of nine Src EGFR FGFR1 FGFR2 ITK NTRK1 NTRK2 MOS systems (17, 18). Using the model of -mutant, erlotinib- family kinase genes, , , , , , , sensitive NSCLC cells, we have performed a systematic ORF-based MST1R RAF1 , and . A subset of these genes can complement loss screen to identify kinase and kinase-related genes whose over- of EGFR activity across multiple EGFR-dependent models. Unbiased expression can complement loss of EGFR activity in an EGFR- gene-expression profiling of cells overexpressing EGFR bypass dependent context. Our findings indicate broad potential for EGFR genes, together with targeted validation studies, reveals EGFR- substitution in the setting of EGFR dependence, with compensatory independent activation of the MEK-ERK and phosphoinositide mechanisms commonly conferring EGFR-independent activation of 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR the PI3K-AKT and MEK-ERK signaling pathways. Importantly, this and MEK restores EGFR dependence in cells expressing each of approach has recovered known mechanisms of erlotinib resistance as the 18 EGFR bypass genes. Together, these data uncover a broad well as identified novel mediators of EGFR bypass in EGFR-mutant spectrum of kinases capable of overcoming dependence on EGFR NSCLC. These data support the idea that the EGFR-dependent and underscore their convergence on the PI3K-AKT and MEK-ERK state can be redundantly driven by diverse genetic inputs that signaling axes in sustaining EGFR-independent survival. commonly converge on shared downstream signaling nodes. Results epidermal growth factor receptor | non-small cell lung cancer | ORF An ORF-Based Screen Identifies 18 Genes Whose Expression Can Substitute for EGFR in an EGFR-Dependent NSCLC Cell Line. To he term “oncogene addiction” has been used to describe the identify genes that complement loss of EGFR activity in the Tphenomenon whereby tumor cells exhibit singular reliance on an oncogene or oncogenic pathway for their survival, despite the accumulation of multiple genetic lesions (1). In non-small Significance cell lung cancer (NSCLC), this principle is perhaps best exem- plified with the finding that epidermal growth factor receptor Non-small cell lung cancers (NSCLCs) harboring mutations in (EGFR) mutations predict response to EGFR tyrosine kinase the epidermal growth factor receptor (EGFR) gene are often inhibitors (TKIs) gefitinib and erlotinib, and thus represent a de- singularly reliant on EGFR activity for tumor cell survival, but pendency in the subset of tumors harboring these alterations (2–6). the genetic basis for this dependence is not fully understood. In However, though EGFR-mutant NSCLCs typically respond dra- this study, we have performed a screen to identify a spectrum matically to EGFR TKIs, clinical responses are not universal, even of kinase genes whose overexpression can overcome NSCLC within this genetically defined cohort, with the rate of objective cells’ reliance on EGFR. Using both unbiased and targeted response estimated to be ∼71% (5, 6). Furthermore, the over- approaches, we demonstrate that these genes commonly by- whelming majority of patients who initially respond to EGFR pass dependence on EGFR through reactivation of downstream inhibitors ultimately develop resistance to therapy (7). A deeper signaling pathways. understanding of the genetic underpinnings of EGFR addiction, and how EGFR-mutant cells can overcome reliance on EGFR, may Author contributions: T.S., A.S., and M.M. designed research; T.S. and M.B. performed research; V.R., B.W., F.H.W., L.A.G., D.A., T.R.G., D.E.R., and A.S. contributed new re- improve clinical outcomes. agents/analytic tools; T.S., V.R., F.P., M.B., M.I., A.D.C., and C.S.P. analyzed data; F.P. Here, we have applied an unbiased screening approach to iden- supervised screening; B.W. visualized data; F.H.W. and L.A.G. guided anaplastic lym- tify genetic modifiers of EGFR dependence in NSCLC. Mounting phoma kinase studies; and T.S. and M.M. wrote the paper. evidence supports the existence of several genetic modifiers of Conflict of interest statement: M.M. was a consultant and received research support from EGFR dependence in EGFR-mutant NSCLC, which can reduce Novartis, and receives research support from Bayer. M.M., L.A.G., and T.R.G. are equity the degree to which these tumors rely on EGFR and thereby holders in, and consultants for, Foundation Medicine. contribute to EGFR TKI resistance (8). Examples include ampli- This article is a PNAS Direct Submission. fication of the MET receptor tyrosine kinase (RTK) (9), activation 1To whom correspondence should be addressed. Email: matthew_meyerson@dfci. of the NF-κB pathway (8), amplification of the HER2 (ERBB2) harvard.edu. GENETICS RTK (10), amplification of the CRKL gene (11), and activation of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. the AXL kinase (12). Notably, MET bypass can be reciprocally 1073/pnas.1412228112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1412228112 PNAS | December 30, 2014 | vol. 111 | no. 52 | 18661–18666 Downloaded by guest on September 23, 2021 setting of EGFR dependence, we performed an ORF over- were assayed for erlotinib sensitivity across multiple drug doses expression screen in an EGFR-dependent NSCLC cell line in the using 72-h growth inhibition assays (Fig. 2A). For comparison, presence of erlotinib. A library of 589 ORFs encoding human the erlotinib-resistant EGFR-mutant positive controls EGFR- kinases and kinase-related proteins [Center for Cancer Systems Δ(E746-A750)-T790M (henceforth EGFR-ex19del-T790M) and Biology (CCSB)/Broad Institute Kinase ORF Collection] (17, EGFR-L858R-T790M were tested in parallel. Ectopic expression 18) was expressed via lentiviral transduction in the EGFR- of 18 of the 19 candidate bypass ORFs was capable of reducing mutant NSCLC cell line, PC9, which is sensitive to EGFR TKIs erlotinib sensitivity relative to cells transduced with an inert ORF A > with an IC50 of ∼30 nM (19). ORF-expressing PC9 cells were (Fig. 2 ). This reduced sensitivity corresponded to a twofold to treated with 300 nM erlotinib, 3 μM erlotinib, or DMSO for 72 h >400-fold shift in IC50 values (Table S1). One primary screening before being assayed for cell viability. Experimental ORFs were hit, YES1, failed to bypass EGFR dependence in our validation screened alongside positive control EGFR ORFs encoding the studies, leaving seven of nine Src family kinase genes confirmed to T790M “gatekeeper” mutation, which can promote resistance to confer the complementation phenotype (Fig. 2A and Table S1); EGFR TKIs (20), in cis with a canonical EGFR activating mu- and notably, this gene scored nearest to the cutoff we used to tation [EGFR-Δ(E746-A750)-T790M and EGFR-L858R-T790M] select ORFs for validation (Fig. 1). We noted that the known (21). Additional positive controls included ORFs encoding acti- EGFR bypass gene MET did not score in our primary screen, vating alleles of several MAPK family members. likely due to failure of the MET expression vector to express MET Cell viability under screening conditions was very low; the me- protein (Fig. S1B). Overall, we estimate that the vast majority of dian relative viability for all experimental ORFs was 12% at the screened ORFs express protein in PC9 cells (Fig. S1 C and D). 300-nM dose and 8% at the 3-μM dose (Fig. 1). Overexpression of The 18 genes capable of bypassing EGFR dependence in PC9 19 ORFs, of the 589 tested, led to a significant increase in viability cells were used to transduce four additional EGFR-mutant of erlotinib-treated PC9 cells, with viability of at least 39% in 300 NSCLC cell line models: the EGFR TKI-sensitive models nM erlotinib and at least 31% in 3 μM erlotinib (Fig. 1). The genes HCC827, HCC2935, and H3255 (22), and the partially sensitive whose ectopic expression led to greater viability in the presence of model HCC2279 (22, 23).
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