New combination therapies for the treatment of KRAS-driven tumors: the interplay between aneuploidy and MAPK signaling

After intensive research to identify KRAS as a human oncogene, the development of selective KRAS-G12C inhibitors has been an important breakthrough in the field of molecular oncology. Beside working as single agents, the G12C specific inhibitors Adagrasib and Sotorasib could be promising partners in a set of combinatorial therapies. Indeed, in aneuploid KRAS-G12C mutated cancer cells, we found that inhibition of the MAPK pathway, together with the chemotherapeutics Topotecan (Topoisomerase I inhibitor) or Etoposide (Topoisomerase II inhibitor), showed synergistic effect and allowed further damage induction by these Topoisomerase inhibitors. The rationale behind our results is the fact that aneuploidy, by the activation of the DNA damage response (DDR), limits the efficacy of Topotecan and Etoposide, impairing the induction of further DNA damage. KRAS-driven cancer cells are characterized by hyper-activated CRAF-MEK-ERK axis and aneuploid cells, upon DDR activation, are even more dependent on this axis. We ameliorated the response to Topotecan and Etoposide in human aneuploid lung adenocarcinoma (LUAD) cells, taking advantage of the parallel inhibition of KRAS by Adagrasib, and analysed the MAPK pathway modulation with these drug combinations. We expect to unveil a new side of KRAS inhibition in the specific area of aneuploid LUAD and to set the basis for a new combinatorial therapy based on the aneuploidy status of different KRAS-driven cancer cells. Since Topotecan, Etoposide and also the new KRAS-G12C specific agents Adagrasib and Sotorasib are all FDA approved drugs and are currently used to treat patients, this work could provide novel insights into the clinics.