Targeting KRAS-G12C in lung cancer: The emerging role of PROTACs in overcoming resistance.

In lung cancer, KRAS mutations, especially the G12C, favor aggressive tumor growth and resistance to standard therapies. Although first-generation inhibitors of KRAS G12C, such as sotorasib and adagrasib, are highly effective in early-phase studies, resistance invariably develops under selective inhibition pressure and rarely leads to sustained long-term treatment benefits. As a novel approach to targeting KRAS mutations in lung cancer, PROTAC (Proteolysis Targeting Chimera) technology is explored in this review. The PROTACs take advantage of the cell's ubiquitin-proteasome system to selectively degrade KRAS proteins, overcoming the dilemma of a lack of traditional binding sites and the means of resistance. We review recent progress with KRAS-specific PROTACs and their mechanisms, clinical application, and effectiveness at targeting primary KRAS oncogenes and secondary drivers and signaling pathways contributing to therapeutic resistance. Also, the synergies between PROTACs and immunotherapies or chemotherapies are further amplified. This review also underscores PROTAC technology's promise to advance precision medicine by providing durable treatment options for KRAS-driven lung cancers. It addresses future directions for optimizing PROTAC efficacy, bioavailability, and patient-specific applications.