2. Academic Validation
  3. Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer

Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer

  • Sci Adv. 2023 Oct 13;9(41):eade3816. doi: 10.1126/sciadv.ade3816.
Atish Mohanty 1,  Arin Nam 1,  Saumya Srivastava 1,  Jeff Jones 2,  Brett Lomenick 2,  Sharad S Singhal 1,  Linlin Guo 1,  Hyejin Cho 3,  Aimin Li 4,  Amita Behal 1,  Tamara Mirzapoiazova 1,  Erminia Massarelli 1,  Marianna Koczywas 1,  Leonidas D Arvanitis 4,  Tonya Walser 1,  Victoria Villaflor 1,  Stanley Hamilton 4,  Isa Mambetsariev 1,  Martin Sattler 5,  Mohd W Nasser 6,  Maneesh Jain 6,  Surinder K Batra 6,  Raffaella Soldi 7,  Sunil Sharma 7,  Marwan Fakih 1,  Saswat Kumar Mohanty 8,  Avijit Mainan 8,  Xiwei Wu 3,  Yihong Chen 9,  Yanan He 9,  Tsui-Fen Chou 2,  Susmita Roy 8,  John Orban 9 10,  Prakash Kulkarni 1,  Ravi Salgia 1
Affiliations

Affiliations

  • 1 Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • 2 Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA.
  • 3 Integrative Genomics Core, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA.
  • 4 Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010,USA.
  • 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 6 Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • 7 Applied Cancer Research and Drug Discovery Division, Translational Genomics Research Institute (TGen) of City of Hope, Phoenix, AZ 850043, USA.
  • 8 Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India.
  • 9 W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA.
  • 10 Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
PMID: 37831779 DOI: 10.1126/sciadv.ade3816
Abstract

Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of Integrin β4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced Wnt expression and activated the Wnt/β-catenin signaling pathway. Thus, silencing both ITGB4 and β-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the Proteasome Inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and β-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130149
    99.93%, KRAS G12C Inhibitor
    Ras