Oncogenic context shapes the fitness landscape of tumor suppression Blair, Lily M. Zafra Martín, María Paz We are grateful to all members of D2G Oncology for expert advice and helpful comments. We thank Explora and The Jackson Laboratory for expert animal care. We would like to acknowledge the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, as well as members of the consortium for their commitment to data sharing (interpretations are the responsibility of the study authors). We thank AstraZeneca, Bristol-Myers Squibb, Revolution Medicines, Merck KGaA, and CureTeq for generously allowing the inclusion of data generated in collaboration with D2G Oncology. L.E.D. is the Burt Gwirtzman Research Scholar in Lung Cancer. D.A.P. and M.M.W. are supported by NIH R01-CA 234349. This work was supported in part by NIH SBIR R44-CA250672. Tumors acquire alterations in oncogenes and tumor suppressor genes in an adaptive walk through the fitness landscape of tumorigenesis. However, the interactions between oncogenes and tumor suppressor genes that shape this landscape remain poorly resolved and cannot be revealed by human cancer genomics 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. We show that the fitness landscape is rugged—the effect of tumor suppressor inactivation often switches between beneficial and deleterious depending on the oncogenic context—and shows no evidence of diminishing-returns epistasis within variants of the same oncogene. These findings argue against a simple linear signaling relationship amongst these three oncogenes and imply a critical role for off-axis signaling in determining the fitness effects of inactivating tumor suppressors. 2023-12-19T13:04:56Z 2023-12-19T13:04:56Z 2023-10-12 journal article Blair, L.M., Juan, J.M., Sebastian, L. et al. Oncogenic context shapes the fitness landscape of tumor suppression. Nat Commun 14, 6422 (2023). [https://doi.org/10.1038/s41467-023-42156-y] https://hdl.handle.net/10481/86348 10.1038/s41467-023-42156-y eng http://creativecommons.org/licenses/by/4.0/ open access Atribución 4.0 Internacional Springer Nature