KRAS

Overview

KRAS (Kirsten rat sarcoma viral oncogene homolog) is a gene that encodes a protein belonging to the RAS family of small GTPases, which are critical regulators of cellular signaling pathways involved in cell proliferation, differentiation, and survival. Mutations in the KRAS gene are among the most common oncogenic alterations found in human cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), where they are present in over 90% of cases. The most prevalent mutation, KRASG12D, leads to constitutive activation of downstream signaling pathways, including the MAPK and PI3K/AKT pathways, promoting tumor growth and resistance to therapies. Due to its pivotal role in cancer biology, KRAS has emerged as a significant target for therapeutic intervention.

Focus of Latest Publications

Recent studies have explored multiple therapeutic strategies targeting KRAS-driven cancers through both direct KRAS inhibition and downstream pathway targeting. Novel SOS1 inhibitors, specifically compounds 78b and 78d, demonstrated high SOS1 binding affinity and potently disrupted the SOS1-KRASG12C interaction, inhibiting nucleotide exchange across WT and multiple KRAS variants in colorectal cancer cells. These compounds induced G1 phase arrest and suppressed MAPK and PI3K signaling pathways, achieving significant tumor growth inhibition (75.1% and 86.2%, respectively) in HCT116 xenograft models without toxicity. Alternative approaches include polyisoprenylated cysteinyl amide inhibitors (PCAIs), which disrupted hyperactive mutant KRAS in pancreatic cancer models; NSL-YHJ-2-27 induced apoptosis, inhibited cancer cell migration by over 90%, and doubled caspase 3/7 activity. Direct degradation approaches using proteolysis-targeting chimeras (PROTACs) targeting KRASG12V induced rapid tumor regression in lung adenocarcinoma through both cancer cell-autonomous and microenvironmental mechanisms.

Adaptive resistance to KRAS inhibition has emerged as a key clinical challenge. A combination therapy approach—pairing selective KRAS inhibitors (RMC-6236/daraxonrasib) with EGFR family inhibitors (afatinib) and STAT3 inhibitors (SD36)—induced complete regression of orthotopic pancreatic tumors with no evidence of tumor resistance for over 200 days posttreatment and was well tolerated in preclinical models. Targeted KRAS degradation in lung adenocarcinoma revealed that disease relapse during prolonged PROTAC treatment stemmed primarily from proteolysis machinery dysregulation, representing distinct resistance mechanisms from those occurring with KRAS inhibition alone. Resistance profiling of KRASG12D inhibitors in pancreatic cancer has highlighted the role of EGFR-mediated RAS-MAPK pathway reactivation as a potential adaptive response mechanism.

Genomic and clinical analyses have identified molecular subtypes and co-mutations that influence treatment outcomes. Among patients with advanced lung adenocarcinoma treated with first-line immunochemotherapy, median progression-free survival did not differ significantly across major KRAS subtypes (G12A, G12C, G12D, G12V), nor was it associated with PD-L1 expression levels. However, STK11 co-mutations were enriched in G12C, G12V, and other subtypes and correlated with shorter progression-free survival. In biliary tract cancer, coexistence of TP53 and KRAS mutations identified a molecular subset with poor overall survival after first-line immunochemotherapy. Pancreatic cancer initiation studies revealed that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations.

Emerging methodologies are advancing KRAS-targeted drug discovery and mutation profiling. Deep learning frameworks applied to directed evolution trajectories identified high-order KRAS mutants with potent activities and uncovered hidden allosteric mechanisms, with case studies demonstrating several designed candidates synthesized with nanomolar biochemical potency. A CRISPR-Cas12a-based assay (RECO-Cas) achieved 0.01% variant allele frequency sensitivity for profiling cfDNA mutations, successfully detecting KRAS point mutations in clinical plasma samples with high sensitivity (90.48%) and specificity (100%), supporting early cancer diagnosis and personalized treatment strategies. Additionally, bifunctional ligands targeting c-MYC and KRAS G-quadruplexes showed potent tumor growth inhibition in vivo, promoting CD8+ and CD4+ T lymphocyte responses.

Key Publications

• NEWJun Clinical Outcomes Associated with Single STK11 Mutations and Those Co-occurring with KEAP1 and KRAS Mutations in Metastatic Non-Small Cell Lung Cancer. (Advances in therapy, 2026, PMID 42377736): "Tumors with STK11 mutations and those co-occurring with KEAP1 and KRAS mutations commonly occur in patients with metastatic non-small cell lung cancer (mNSCLC)."
• Jun Discovery of Highly Potent and Selective SOS1 Inhibitors for the Treatment of KRAS-Driven Colorectal Cancer. (Journal of medicinal chemistry, 2026, PMID 42247371): "The guanine nucleotide exchange factor SOS1 has emerged as an attractive therapeutic target for various KRAS-driven tumors."
• Jun The anticancer effects of PCAIs in pancreatic cancer cells involve MAPK and PI3K/AKT pathways hyperactivation. (Oncotarget, 2026, PMID 42233520): "There remains an unmet need for effective drugs targeting KRAS-driven cancers."
• Jun A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42224594): "a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment."
• May Targeted KRASG12V Degradation in vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis. (Cancer research, 2026, PMID 42200804): "Here, we developed a preclinical LUAD mouse model and demonstrated that targeted oncogenic KRAS degradation induces rapid tumor regression primarily due to cancer cell-autonomous mechanisms."
• May Navigating high-order protein fitness landscapes via deep learning on directed evolution trajectories. (Proceedings of the National Academy of Sciences of the United States of America, 2026, PMID 42190010): "Applied to the cancer target KRAS, DENet-guided screening systematically identified high-order mutants with potent activities and uncovered hidden allosteric mechanisms."
• May Coexistence of TP53 and KRAS mutations identifies a molecular subset of biliary tract cancer with poor overall survival after first-line immunochemotherapy. (European journal of cancer (Oxford, England : 1990), 2026, PMID 42190397): "Coexistence of TP53 and KRAS mutations identifies a molecular subset of biliary tract cancer with poor overall survival after first-line immunochemotherapy."
• May Single-nucleotide variant profiling in liquid biopsy with RECO-Cas. (Science advances, 2026, PMID 42172311): "Using the assay, we detect KRAS, EGFR, and PIK3CA point mutations in cfDNA from clinical plasma samples, demonstrating high sensitivity (90.48%) and excellent specificity (100%)."
• Jun Human pancreatic progenitor organoids define genetic and epigenetic barriers to early PDAC transformation. (Developmental cell, 2026, PMID 42161274): "We demonstrate that CDKN2A loss, which is nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, whereas SMAD4 loss promotes tumor progression."
• May Gel-Based NMR Method for Observing Submicrosecond Protein Dynamics at Atomic Resolution. (The journal of physical chemistry letters, 2026, PMID 42117532): "This generalized NASR approach is demonstrated for K-Ras and other proteins exhibiting internal dynamics with variable amplitudes on a wide range of time scales."