Targeting KRAS mutant cancers: from druggable therapy to drug resistance
KRAS mutations are the most frequently mutated oncogene, occurring in a variety of tumor types.
Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS‑mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.
KRAS mutations drive aggressive disease and poor prognosis, and new therapies targeting KRAS could significantly improve patient outcomes.
Evidence level: Sejtvonalas. Laboratóriumi sejtekben vizsgálták.
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