2. Academic Validation
  3. Daraxonrasib, a pan-RAS inhibitor, selectively inhibits osteosarcomas with activated KRAS by halting AKT signaling and matrix metalloprotease activity

Daraxonrasib, a pan-RAS inhibitor, selectively inhibits osteosarcomas with activated KRAS by halting AKT signaling and matrix metalloprotease activity

  • PLoS One. 2025 Aug 8;20(8):e0329946. doi: 10.1371/journal.pone.0329946.
Okkeun Jung 1 2,  Angelene Soto 3,  Andrew L Wolfe 2 3 4 5 6,  Shahana S Mahajan 1 2 3 5 7
Affiliations

Affiliations

  • 1 Department of Medical Laboratory Sciences, Hunter College, City University of New York, New York, New York, United States of America.
  • 2 Ph.D. Program in Biology (Molecular, Cellular, and Developmental Biology Sub-Program), The Graduate Center of the City University of New York, New York, New York, United States of America.
  • 3 New York Research and Mentoring for Postbaccalaureates at Hunter College of the City University of New York, New York, New York, United States of America.
  • 4 Department of Biological Sciences, Hunter College of the City University of New York, New York, New York, United States of America.
  • 5 Ph.D. Program in Biochemistry, The Graduate Center of the City University of New York, New York, New York, United States of America.
  • 6 Department of Pharmacology, Weill Cornell Medical College, New York, New York, United States of America.
  • 7 Brain Mind Research Institute, Weill Cornell Medical College, New York, New York, United States of America.
PMID: 40779492 DOI: 10.1371/journal.pone.0329946
Abstract

KRAS mutations, which induce proliferative signaling driving many human cancers, are detectable in a small subset of osteosarcoma patients. The recently developed pan-KRAS inhibitor daraxonrasib, also known as RMC-6236, is capable of targeting a wide array of KRAS mutations and shows promise against pancreatic and lung cancers. However, the efficacy and mechanisms of action of daraxonrasib in osteosarcoma (OS) remain unclear. We evaluated the effects of daraxonrasib on the viability, proliferation, and metastatic potential of wild-type and KRAS mutant OS cells. We assayed the effects of treatment on downstream targets using qPCR, immunoblotting, and activity assays to explore the underlying mechanism by which daraxonrasib selectively suppresses the metastatic potential of KRAS mutant osteosarcoma. Finally, we investigated how the increased prevalence of GTP-bound KRAS enhanced the sensitivity of KRAS wild-type osteosarcoma cells to daraxonrasib using siRNA targeting RASA1. Daraxonrasib selectively attenuated the proliferation and migratory ability of KRAS mutant HOS-143B cells without affecting KRAS wild-type controls. Additionally, daraxonrasib suppressed the expression of the matrix metalloproteases MMP9 and MMP1, which promote cell motility and metastasis. Daraxonrasib selectively inhibited the Akt/ETS1 pathway in HOS-143B cells, whereas no such effect was observed in HOS cells. HOS cells were sensitized to daraxonrasib by knocking down the GTPase-activating protein RASA1. In osteosarcoma, KRAS inhibition decreased MMP1, MMP9, and Akt/ETS1 signaling. Daraxonrasib is a promising agent for treating osteosarcoma with KRAS mutations.

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