Millions of lung tumors harboring KRAS, BRAF, EGFR, and tumor suppressor alterations from genetically engineered mouse models

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.