Targeting KRAS in Cancer: Advances in Precision Oncology and Drug Development

KRAS-targeted therapy in oncology: From four decades of failed attempts to a new era of precision medicine

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.

KRAS G12C-Targeted Therapy Strategy for Lung Cancer: Mechanism, Clinical Practice and Challenges

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.

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies.

KRAS is one of the most frequently mutated oncogenes in human cancers, with KRAS G12D representing the predominant mutation in pancreatic ductal adenocarcinoma and a major driver of colorectal and lung cancers. Although KRAS was long considered "undruggable" due to structural and biochemical constraints, the discovery of the switch-II pocket enabled the development of direct KRAS inhibitors, leading to the clinical success of KRAS G12C-targeted therapies. Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805. Pan-RAS and pan-KRAS inhibitors have emerged as a promising strategy to overcome the limitations of mutation-specific KRAS inhibitors, including restricted mutation coverage and acquired resistance. Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment.

From KRAS inhibition to tumor adaptation: mechanistic layers of resistance and therapeutic strategies.

BACKGROUND KRAS is a central oncogenic driver in multiple solid malignancies, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, and colorectal cancer. Activating KRAS mutations, together with co-mutations and gene-dosage alterations, reprogram signaling pathways, cellular metabolism, and the tumor microenvironment, thereby promoting aggressive tumor behavior and therapeutic resistance. Despite recent advances, including KRAS G12C inhibitors and emerging agents targeting G12D, pan-RAS(ON), and nucleotide-free RAS, clinical responses remain limited in many KRAS-mutant contexts due to rapid and multifaceted resistance. AIM OF REVIEW This review aims to examine the mechanisms underlying resistance to KRAS-targeted therapies and to provide an integrated perspective on how adaptive tumor responses limit the durability of KRAS inhibition. KEY SCIENTIFIC CONCEPTS OF REVIEW Selective pressure from KRAS-targeted therapies drives adaptive tumor evolution through on-target alterations, rewiring of signaling networks, and non-genetic changes in cell state and the tumor microenvironment. This review synthesizes current knowledge on these resistance mechanisms and highlights emerging therapeutic strategies, including rational combination approaches, enhanced RAS pathway suppression, targeted protein degradation, and KRAS-directed immunotherapies. By integrating recent preclinical and clinical advances, this work provides a comprehensive framework for understanding resistance and improving the durability of KRAS pathway inhibition in cancer.

KRAS-Targeted Therapy in Non–Small Cell Lung Cancer: Current Standards, Resistance Mechanisms, and Emerging Therapeutic Strategies

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic alterations in non–small cell lung cancer (NSCLC), particularly in lung adenocarcinoma, and for decades were regarded as therapeutically intractable. The development of covalent KRAS G12C inhibitors has changed this paradigm, establishing direct KRAS inhibition as a clinically actionable strategy. Sotorasib and adagrasib have demonstrated antitumor activity in previously treated KRAS G12C–mutated advanced NSCLC and are now important targeted options following prior systemic therapy. However, the clinical benefit of current monotherapy remains limited. Randomized trials have shown improved progression-free survival compared with docetaxel, but a definitive overall survival advantage has not been established. Acquired resistance is common and biologically heterogeneous, involving secondary KRAS alterations, KRAS amplification, receptor tyrosine kinase activation, downstream Mitogen-Activated Protein Kinase (MAPK) or Phosphoinositide 3-Kinase (PI3K) pathway reactivation, histologic transformation, and adaptive feedback signaling. Outcomes are further influenced by central nervous system involvement, treatment-related toxicity, prior immunotherapy exposure, and co-occurring genomic alterations such as TP53, STK11, and KEAP1. Emerging strategies include more potent KRAS G12C inhibitors, active-state RAS inhibitors, pan-RAS approaches, KRAS G12D inhibitors and degraders, rational combination regimens, and KRAS-directed immunotherapies. Direct KRAS inhibition has thus transformed KRAS G12C–mutated NSCLC from a previously undruggable subtype into a targetable disease, but durable disease control remains an unmet need. Future progress will require comprehensive molecular profiling, broader targeting of non–G12C KRAS variants, improved intracranial efficacy, resistance-informed combinations, equitable access to molecular diagnostics, and randomized evidence demonstrating meaningful survival and quality-of-life benefits.

KRAS-Targeted Therapies in NSCLC: Resistance, Combination Strategies, and Emerging Clinical Paradigms