ArticleMolecular cancer therapeutics2024
The SOS1 Inhibitor MRTX0902 Blocks KRAS Activation and Demonstrates Antitumor Activity in Cancers Dependent on KRAS Nucleotide Loading.
Article in Molecular cancer therapeutics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Review
- Targeted therapeutic strategies forTranslational lung cancer research · 2026Review
- Benefits and challenges of adding BKM120 to a BI-3406 plus trametinib combination therapy.BMC cancer · 2026Article
- Combining cutting edge computational and experimental methods for targeting KRAS mutations in non-small cell lung cancer.Expert opinion on drug discovery · 2026Review
- Computational insights on the molecular interplay between KRas (G12D mutation) and SOS1 modulated by the inhibitor BI-3406.PLoS computational biology · 2026Article
- SOS1: tracking the evolving path from promising to actionable therapeutic target in RAS-dependent cancers.Molecular cancer · 2026Review
- BRAF inhibitor resistance in melanoma: from resistance mechanisms to therapeutic innovations.Molecular biomedicine · 2026Review
- Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C.Nature communications · 2026Article
- Emerging Therapeutic Landscapes for KRAS-Mutant Pancreatic Ductal Adenocarcinoma: Beyond the "Undruggable" Paradigm.The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology · 2026Review
- Tumor suppressor genes and KRAS G12C inhibitor resistance in non-small cell lung cancer.iScience · 2026Review
- Disrupting the KRAS-SOS1 protein-protein interaction: mechanistic rationale for pan-KRAS pathway suppression and combination therapy.Frontiers in chemistry · 2026Review
- Modeling response to the KRAS-G12C inhibitor AZD4625 in KRASBritish journal of cancer · 2026Article
- SOS1 inhibition suppresses the emergence of osimertinib resistance to generate a durable response inScience signaling · 2025Article
- Guanine Nucleotide Exchange Factors and Small GTPases: Their Regulation and Functions, Diseases, and Therapeutic Targets.MedComm · 2025Review
- Novel paradigms in KRAS targeting: Unveiling strategies to combat drug resistance.Chinese medical journal · 2025Review
- Review
- A transcriptomic, proteomic, and functional genetic atlas dissects neurofibromin function in the peripheral nervous system.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Review
- A Phase Ia/b study of MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in patients with RAS mutant advanced colorectal cancer (MErCuRIC).BMC cancer · 2025Article
- Elucidating the therapeutic potential of indazole derivative bindarit against K-ras receptor: AnBiochemistry and biophysics reports · 2025Article
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34 authors.
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Abstract
KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1 and PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy.
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