Oncogenic context shapes the fitness landscape of tumor suppression

Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the features of this landscape remain poorly understood and cannot be revealed by human cancer genotyping alone. Here, we use a multiplexed, autochthonous mouse platform to model and quantify the initiation and growth of more than one hundred genotypes of lung tumors across four oncogenic contexts: KRAS G12D, KRAS G12C, BRAF V600E, and EGFR L858R. The resulting fitness landscape is rugged (the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context), shows no evidence of diminishing-returns epistasis within variants of the same oncogene, and is inconsistent with expectations of a simple linear signaling relationship among these three oncogenes. Our findings suggest that tumor suppressor effects are strongly context-specific, which limits the set of evolutionary paths that can be taken through the fitness landscape. ### Competing Interest Statement L.M.B., J.M.J., L.S., V.B.T., G.D.W., M.G., I.K.L., E.A.A., G.G., D.A., J.J.M., and M.J.R. are employees and shareholders of D2G Oncology. I.P.W. is a co-founder, employee, and shareholder of D2G Oncology. D.A.P. and M.M.W. are co-founders, shareholders, members of the board of directors, and compensated scientific advisors of D2G Oncology. I.P.W., D.A.P., and M.M.W. are co-inventors of patents relating to technologies for autochthonous mouse model of human cancer, which D2G Oncology. has exclusively licensed from Stanford University. D.D. and A.C. are employees and shareholders of Cellecta. L.E.D. is a scientific advisor and holds equity in Mirimus. L.E.D., M.P.Z. and Cornell University have licensed technology described in this manuscript. P.D.S. is an employee and shareholder of AstraZeneca. K.P. is co-inventor on a patent related to EGFR T790M mutation testing issued, licensed, and with royalties paid from MSKCC/MolecularMD. K.P. reports grants to her institution from Boehringer Ingelheim, AstraZeneca, Roche/Genentech, and D2G Oncology, and consulting fees from AstraZeneca and Janssen. All remaining authors declare no competing financial interests.