A genetic interaction analysis identifies cancer drivers that modify EGFR dependency.
A large number of cancer drivers have been identified through tumor sequencing efforts, but how they interact and the degree to which they can substitute for each other have not been systematically explored. To comprehensively investigate how cancer drivers genetically interact, we searched for modifiers of epidermal growth factor receptor (EGFR) dependency by performing CRISPR, shRNA, and expression screens in a non-small cell lung cancer (NSCLC) model. We elucidated a broad spectrum of tumor suppressor genes (TSGs) and oncogenes (OGs) that can genetically modify proliferation and survival of cancer cells when EGFR signaling is altered. These include genes already known to mediate EGFR inhibitor resistance as well as many TSGs not previously connected to EGFR and whose biological functions in tumorigenesis are not well understood. We show that mutation ofPBRM1, a subunit of the SWI/SNF complex, attenuates the effects of EGFR inhibition in part by sustaining AKT signaling. We also show that mutation of Capicua (CIC), a transcriptional repressor, suppresses the effects of EGFR inhibition by partially restoring the EGFR-promoted gene expression program, including the sustained expression of Ets transcription factors such asETV1Together, our data provide strong support for the hypothesis that many cancer drivers can substitute for each other in certain contexts and broaden our understanding of EGFR regulation.
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Department of Genetics, Program in Virology, Howard Hughes Medical Institute, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Sida
S
Liao
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Department of Genetics, Program in Virology, Howard Hughes Medical Institute, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Teresa
T
Davoli
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Department of Genetics, Program in Virology, Howard Hughes Medical Institute, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Yumei
Y
Leng
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Department of Genetics, Program in Virology, Howard Hughes Medical Institute, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Mamie Z
MZ
Li
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Department of Genetics, Program in Virology, Howard Hughes Medical Institute, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Qikai
Q
Xu
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Department of Genetics, Program in Virology, Howard Hughes Medical Institute, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Stephen J
SJ
Elledge
D000230:Adenocarcinoma / Q000235:genetics* / Q000503:physiopathology*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D009687:Nuclear Proteins / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D011799:Quinazolines; D012097:Repressor Proteins; D014157:Transcription Factors; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D000077156:Gefitinib
EGFR; cancer drivers; genetic interaction