Jul 2026· Theoretical and Natural Science· 0 citations
TL;DR
This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision-making and further research in this field.
Abstract
Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutations represent the most common driver alterations in non-small cell lung cancer and were long considered "undruggable" due to the lack of a suitable binding pocket on the protein surface. Recent structural breakthroughs have identified the Switch-II allosteric pocket, facilitating the development and clinical application of several covalent inhibitors—including Sotorasib, Adagrasib, and Divarasib—which have substantially improved outcomes for patients harboring this mutation. However, primary and acquired resistance remain major obstacles to long-term efficacy, with resistance mechanisms involving RTK-mediated adaptive signaling reactivation, aberrant PI3K–AKT–mTOR pathway activation, secondary genetic alterations, and other factors. Moreover, intratumoral heterogeneity, characterized by the coexistence of sensitive and resistant subclones, further complicates therapeutic responses. To overcome these challenges, combination strategies have become a major research focus, including the pairing of KRAS G12C inhibitors with immune checkpoint inhibitors, RTK-targeted agents, SHP2 inhibitors, or MEK inhibitors, aiming to block escape pathways and enhance antitumor immunity. Future directions emphasize optimizing combination regimens, exploring personalized immunotherapy, and developing next‑generation inhibitors to prolong survival. This review systematically summarizes the molecular mechanisms driving KRAS G12C‑mutant lung cancer, clinical applications of targeted drugs, resistance and heterogeneity challenges, and progress in combination therapy, providing a reference for clinical decision‑making and further research in this field.
Direct KRAS inhibition has transformed KRAS G12C–mutated NSCLC from a previously undruggable subtype into a targetable disease, but durable disease control remains an unmet need.
Kohei Eguchi, Yukito Kajita, Muraoka Suguru et al.· Journal of Clinical Question· 0 citations
Kirsten rat sarcoma viral oncogene homolog (KRAS), a member of the small GTPase family, is the most frequently mutated RAS isoform in human cancers. It drives tumorigenesis and progression in various malignancies, including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), and colorectal cancer (CRC), and has long been considered an “undruggable” target. Recent advances in mutant-selective KRAS inhibition have reshaped this view, but therapeutic responses remain limited by adaptive resistance, tumor heterogeneity, and context-dependent signaling dependencies. This review focuses on how allele-specific biochemical properties, tissue context, and co-mutational backgrounds shape KRAS signaling output, tumor progression, therapeutic response, and resistance. We further discuss current diagnostic approaches and therapeutic strategies, ranging from direct mutant-selective inhibitors to pathway-targeted combinations, degraders, immunotherapies, RNA-based approaches, and exosome-mediated delivery. Finally, we highlight key challenges including adaptive resistance, tumor heterogeneity, allele-specific druggability, and the need for biomarker-guided combination strategies. Together, this review provides a framework for understanding KRAS-mutant cancers as biologically diverse diseases and for guiding the development of more precise and durable therapeutic strategies.
These breakthroughs have validated direct KRAS inhibition as an effective therapeutic strategy, however, durable clinical responses remain limited by intrinsic and acquired resistance, pathway reactivation, tumour heterogeneity, and the lack of effective therapies for non-G12C KRAS mutations.
Pasham Uma, Dandotikar Neha, R. Manisha et al.· International Journal of Inn...· 0 citations
This review synthesizes current knowledge on KRAS resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies.
Rawan Salih, F. Sirajudeen, Mohamed Rahmani· Journal of Advanced Research· 0 citations
Mutations in the KRAS (Kirsten Rat Sarcoma Viral Proto-oncogene) gene represent among the most prevalent oncogenic drivers in human malignancies, occurring in approximately 25% of all solid tumors. For more than four decades, KRAS was considered pharmacologically intractable due to the protein's picomolar affinity for GTP/GDP and the absence of accessible allosteric binding sites. The identification of the switch-II pocket (S-IIP) and subsequent development of mutation-selective covalent inhibitors targeting the KRAS G12C mutant fundamentally altered this paradigm. Sotorasib and adagrasib, the first approved KRAS G12C inhibitors, have demonstrated meaningful clinical activity in NSCLC and, in combination with anti-EGFR agents, in colorectal cancer. However, both drugs achieve only modest objective response rates of 30–43% in NSCLC with median progression-free survival of approximately six months, substantially below outcomes achieved with targeted therapies directed at EGFR or ALK. Acquired resistance emerges rapidly through on-target KRAS mutations, bypass signaling, and phenotypic plasticity. An expanding pipeline of next-generation agents targeting G12D, G12V, and pan-KRAS approaches offers the first plausible therapeutic options for pancreatic and other KRAS-driven cancers beyond G12C. This narrative review critically evaluates the biological basis of KRAS oncogenesis, the pharmacological obstacles that delayed drug development, the clinical performance and limitations of approved inhibitors, resistance mechanisms and rational combination strategies, and the evidence base and uncertainties surrounding next-generation therapeutic approaches.
Arshinnikova Anna S., Tararina Valeria V., Zuban Polina A. et al.· International Journal of Sci...· 0 citations
KRAS driver mutations have classically been considered undruggable by direct inhibitors in non-small cell lung cancer (NSCLC) as well as other solid tumors. However, recent advances have led to the first successful direct KRAS inhibitors, beginning with the development of KRASG12C inhibitors targeting the inactive GDP-bound state of KRAS. These initial KRASG12C (OFF) inhibitors demonstrated real but modest activity in KRASG12C-mutated mNSCLC. The development of more potent optimized KRASG12C (OFF) inhibitors has sought to improve upon the clinical activity of the initial raft of KRASG12C (OFF) inhibitors. Combination therapy with PD-1 inhibitors, as well as other classes of drugs, is also under intense investigation in NSCLC and other solid tumors. Nevertheless, primary and acquired resistance, as well as a variable and peculiar tendency to autoimmune hepatitis, have complicated efforts to develop this class of inhibitors in KRASG12C-mutated mNSCLC. In parallel, new direct inhibitor classes have emerged recently, including tri-complex ON-state inhibitors and dual-state ON/OFF inhibitors capable of targeting not only KRASG12C but also other KRAS mutations, as well as panKRAS and panRAS strategies. These agents have the potential to broaden the activity of initial KRASG12C (OFF) inhibitors and to avoid certain mechanisms of resistance and toxicity, but remain early in development with limited data. The KRAS therapeutic landscape is evolving rapidly, with many promising competing strategies each seeking to distinguish itself in an increasingly crowded therapeutic landscape.
Tämer El Saadany, Núria Aeschlimann, A. Sacher· Cancer Journal· 0 citations
