Oncogenic context shapes the fitness landscape of tumor suppression

Lily M. Blair, Joseph M. Juan, Lafia Sebastian, Vy B. Tran, Wensheng Nie, Gregory D. Wall, Mehmet Gerceker, Ian K. Lai, Edwin A. Apilado, Gabriel Grenot, David Amar, Giorgia Foggetti, Mariana Carmo, Zeynep Ugur, Debbie Deng, Alex Chenchik, Maria Paz Zafra, Lukas E. Dow, Katerina Politi, Jonathan J. MacQuitty, Dmitri A. Petrov, Monte M. Winslow, Michael J. Rosen () and Ian P. Winters ()
Additional contact information
Lily M. Blair: D2G Oncology
Joseph M. Juan: D2G Oncology
Lafia Sebastian: D2G Oncology
Vy B. Tran: D2G Oncology
Wensheng Nie: D2G Oncology
Gregory D. Wall: D2G Oncology
Mehmet Gerceker: D2G Oncology
Ian K. Lai: D2G Oncology
Edwin A. Apilado: D2G Oncology
Gabriel Grenot: D2G Oncology
David Amar: D2G Oncology
Giorgia Foggetti: Yale School of Medicine
Mariana Carmo: Yale School of Medicine
Zeynep Ugur: Yale School of Medicine
Debbie Deng: Cellecta
Alex Chenchik: Cellecta
Maria Paz Zafra: Weill Cornell Medicine
Lukas E. Dow: Weill Cornell Medicine
Katerina Politi: Yale School of Medicine
Jonathan J. MacQuitty: D2G Oncology
Dmitri A. Petrov: Stanford University
Monte M. Winslow: Stanford University School of Medicine
Michael J. Rosen: D2G Oncology
Ian P. Winters: D2G Oncology

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-42156-y

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