KRAS and MYC synergistic inhibition: a powerful strategy targeting KRAS-mutant cancers

KRAS is a critical proto-oncogene that encodes a protein functioning as a pivotal molecular switch in intracellular signaling. Both KRAS mutations and MYC dysregulation are key drivers of tumor progression and have historically been regarded as “undruggable” targets. Emerging evidence underscores that the coordinated activation of KRAS and MYC cooperatively fuels tumorigenesis, suggesting that dual inhibition of these oncogenes may constitute a synergistic therapeutic approach for KRAS-mutant cancers. However, the mechanistic basis underlying the effective combined targeting of KRAS and MYC remains poorly defined, largely due to the complexity of their functional interplay. This review examines their collaborative roles in metabolic reprogramming, epigenetic remodeling, and shaping an immunosuppressive tumor microenvironment through crosstalk with immune cells. It also surveys current and emerging anti-KRAS strategies and discusses the challenge of therapy resistance, particularly in the setting of MYC dysregulation. Since resistant tumors often circumvent KRAS inhibition by reactivating MYC to sustain proliferation and survival, interventions that concurrently target these adaptive pathways may hold promise for overcoming resistance in KRAS-driven malignancies.