Blockade of the KRAS-FOSL1 axis elicits DNA damage repair deficiency exploitable with local and systemic genotoxic therapies

The clinical approval of direct KRAS inhibitors represents a milestone in precision oncology. Nonetheless, resistance heterogeneity limits durable clinical responses and impedes the nomination of a ‘‘one-size-fits-all’’ strategy for combination therapies. We circumvent this impasse by uncovering a core vulnerability elicited by KRAS blockade which transcends tissue origin, KRAS mutation, intrinsic KRASi sensitivity, and clinically relevant concurrent mutations. Specifically, we show that KRAS inhibition elicits a functional deficit in DNA damage repair by transcriptionally repressing homologous recombination. This BRCAness phenotype constitutes a conditional synthetic lethality to PARP inhibitors and radiotherapy, which synergize with single KRAS blockade and significantly delay the onset of secondary resistance. Integrative analyses identify the transcription factor FOSL1 as an upstream regulator of homologous recombination whose depletion sensitizes to PARP inhibition and radiotherapy. Collectively, we define a translational trajectory for the combination of KRAS inhibitors with clinically approved DNA-damaging agents as a therapeutic strategy treatment potentially expandable to most, if not all, mutant KRAS cancers.