KRAS is one of the most frequently mutated oncogenes in human tumors. Nevertheless, despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat and eradicate KRAS-mutant malignancies. We performed a cell line-based compound screen and identified strong synergistic interactions between cell cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS- and BRAF-mutant cancer cells display intrinsic genotoxic stress, leading to tonic activation Chk1- and MK2. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to the induction of a mitotic catastrophe in KRAS-mutant cells. This druggable synergistic interaction is validated using xenograft models, as well as an autochthonous model of KRAS-driven lung adenocarcinoma. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS-mutant tumor cells directly isolated from patients. These results implicate combined Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.