Aug 2026· Journal of Advanced Research· 0 citations· 149 references
Medicine
TL;DR
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.
Abstract
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 mutations are among the most prevalent oncogenic drivers in human malignancies and are increasingly recognized as critical determinants of tumor progression, immune evasion, and therapeutic resistance. Beyond its canonical role in promoting oncogenic signaling, accumulating evidence indicates that KRAS functions as a regulator of the tumor immune microenvironment, influencing antigen presentation, inflammatory signaling, metabolic adaptation, stromal remodeling, and responsiveness to immunotherapy. This review synthesizes current knowledge regarding the biological and immunological consequences of oncogenic KRAS across major cancer types, including non-small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma, with emphasis on the mechanisms by which KRAS-driven tumors establish and maintain immunosuppressive microenvironments. Recent advances in immunopeptidomics and precision immuno-oncology have identified KRAS-derived neoantigens that can be targeted through T-cell receptor-engineered therapies, bispecific antibodies, and therapeutic vaccines. Concurrently, the clinical development of direct KRAS inhibitors, including sotorasib and adagrasib, has demonstrated meaningful antitumor activity while revealing adaptive resistance mechanisms that frequently limit durable responses. Emerging evidence suggests that effective therapeutic strategies will require integrating KRAS-targeted therapies with immune checkpoint blockade and other immunomodulatory approaches to overcome tumor-intrinsic and microenvironment-mediated resistance. Collectively, current evidence supports a paradigm in which KRAS functions not only as an oncogenic driver but also as a regulator of tumor-immune interactions, shaping therapeutic responsiveness and providing opportunities for biomarker-guided and combination-based immunotherapy in KRAS-mutant cancers.
M. Ashrafizadeh, Noushin Nabavi, Yifei Xu· Cancer Biome and Targeted Th...· 0 citations
Rational combination strategies are outlined that simultaneously target the RAS/MAPK axis and key TME vulnerabilities, such as immunotherapy combinations, CAF reprogramming, and ECM normalization, to overcome stromal-mediated resistance and achieve deeper, more sustained clinical responses.
Wen-Hao Ma, Xing-Yu Guo, Xiu-Ting Liu· Cancer Advances· 0 citations
Direct KRAS inhibitors have established mutant KRAS as a clinically actionable target, yet adaptive resistance remains a major barrier to durable responses. To identify therapeutically actionable resistance mechanisms, we performed an unbiased in vivo CRISPR activation screen in an autochthonous lung adenocarcinoma model, identifying the receptor tyrosine kinase AXL as a dominant adaptive resistance driver. Pharmacologic AXL inhibition enhanced the efficacy of both allele-specific inhibition and the RAS(ON) multi-selective inhibitor daraxonrasib across lung and pancreatic cancer models, resulting in deeper and more durable suppression of MAPK signaling and improved tumor control. Beyond tumor-intrinsic effects, combined KRAS and AXL inhibition remodeled the tumor immune microenvironment, promoting an IFNγ-responsive program, increased recruitment of cytotoxic T cells and sensitization to FAS-mediated apoptosis. Collectively, our findings identify AXL as a convergence point for adaptive resistance to KRAS inhibition and provide a mechanistically informed combination strategy to extend the durability of KRAS-directed therapies. Statement of Significance An unbiased in vivo functional (CRISPR activation) screen identifies AXL as a convergence point for adaptive resistance to KRAS inhibition. By integrating adaptive response to KRAS inhibition with anti-tumor immunity, AXL represents a mechanistically actionable vulnerability whose inhibition deepens and prolongs responses to both allele-specific and pan-KRAS-targeted therapies.
F. Thege, A. Kramer, Norbert Kreisz et al.· bioRxiv· 0 citations
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
Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies because of aggressive tumor biology, pervasive therapeutic resistance, rapid adaptive reprogramming, and a profoundly immunosuppressive tumor microenvironment. This review summarizes recent advances in KRAS-targeted therapies, DNA damage response (DDR)-directed strategies, immune-redirection platforms, and tumor microenvironment modulation. Methods: We conducted a narrative review of peer-reviewed publications, clinical trial reports, trial registries, and selected conference data addressing emerging therapeutic strategies for PDAC. Results: KRAS-targeted therapies, including KRAS G12D-selective and multi-selective RAS(ON) inhibitors, have demonstrated substantial preclinical and emerging clinical activity while revealing diverse mechanisms of adaptive resistance. DDR-directed approaches are expanding beyond BRCA-mutated disease toward functional homologous recombination deficiency, replication stress, and synthetic lethality. In parallel, bispecific antibodies, T-cell engagers, and CAR-T-cell therapies have generated preliminary evidence of antitumor activity, although stromal exclusion, antigen heterogeneity, and immune suppression remain major barriers. These advances indicate that therapeutic resistance in PDAC is a dynamic process involving interconnected oncogenic, genomic, stromal, metabolic, and immune mechanisms. Conclusions: Future progress will require biologically informed treatment frameworks integrating complementary therapeutic modalities according to baseline tumor biology and treatment-induced adaptive states, supported by longitudinal biomarkers and rational clinical trial design.
Jun Kim, Seounghun Kang· Pharmaceutics· 0 citations
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.
Xizhi Zha· Theoretical and Natural Scie...· 0 citations