KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers. Display omitted •The PreCISE software accurately captures synergistic drug interactions•Combined Chk1/MK2 inhibition synergistically induces apoptosis in KRAS-mutant cancer•KRAS-mutant tumor cells display a tonic activation of the DNA damage response•Autochthonous Kras-driven tumors display non-oncogene addiction to Chk1 and MK2 PreCISE, a new platform that reliably captures synergic drug interactions from large-scale cell-line-based screens, shows that simultaneous inhibition of the cell-cycle checkpoint kinases Chk1 and MK2 effectively eradicates KRAS-mutant cancer cells directly isolated from patients and in distinct Kras-driven murine tumor models.