ABSTRACT
Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type and the discovery of oncogene mutations has led to the development of targeted therapies and better clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens with quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Through the generation of hundreds of diverse combinations of tumor suppressor alterations, we demonstrate that inactivation of suppressors of the RAS and PI3K pathways drive the development of oncogene- negative lung adenocarcinoma. Pathway-level human genomic data analysis and histology identified RAS/MAPK and PI3K pathway activation as a common event in oncogene-negative human lung adenocarcinomas. We demonstrate that oncogene-negative tumors and cell lines with activated RAS/MAPK and PI3K pathways are vulnerable to pharmacological inhibition of these signaling axes. Collectively, these results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma.
STATEMENT OF SIGNIFICANCE Many lung adenocarcinomas do not have mutations in known proto-oncogenes, and as a result, targeted therapies are unavailable for treating these patients. Here, we uncover driver pathways in a subset of these oncogene-negative lung adenocarcinomas and demonstrate the therapeutic value of inhibiting these pathways.
Competing Interest Statement
S.K.C. receives grant support from Ono Pharma. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx, and Ono Pharmaceuticals. C.S is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristo Myers Squibb, Celgene, AstraZeneca, Illumina, Amgen, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. D.A.P. and M.M.W. are founders of, and hold equity in, D2G Oncology Inc.
Footnotes
↵8 These authors contributed equally
CONFLICT OF INTERESTS S.K.C. receives grant support from Ono Pharma. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx, and Ono Pharmaceuticals. C.S is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Amgen, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. D.A.P. and M.M.W. are founders of, and hold equity in, D2G Oncology Inc.