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Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer.
Mohanty, Atish; Nam, Arin; Srivastava, Saumya; Jones, Jeff; Lomenick, Brett; Singhal, Sharad S; Guo, Linlin; Cho, Hyejin; Li, Aimin; Behal, Amita; Mirzapoiazova, Tamara; Massarelli, Erminia; Koczywas, Marianna; Arvanitis, Leonidas D; Walser, Tonya; Villaflor, Victoria; Hamilton, Stanley; Mambetsariev, Isa; Sattler, Martin; Nasser, Mohd W; Jain, Maneesh; Batra, Surinder K; Soldi, Raffaella; Sharma, Sunil; Fakih, Marwan; Mohanty, Saswat Kumar; Mainan, Avijit; Wu, Xiwei; Chen, Yihong; He, Yanan; Chou, Tsui-Fen; Roy, Susmita; Orban, John; Kulkarni, Prakash; Salgia, Ravi.
Affiliation
  • Mohanty A; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Nam A; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Srivastava S; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Jones J; Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA.
  • Lomenick B; Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA.
  • Singhal SS; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Guo L; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Cho H; Integrative Genomics Core, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA.
  • Li A; Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010,USA.
  • Behal A; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Mirzapoiazova T; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Massarelli E; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Koczywas M; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Arvanitis LD; Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010,USA.
  • Walser T; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Villaflor V; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Hamilton S; Department of Pathology, City of Hope National Medical Center, Duarte, CA 91010,USA.
  • Mambetsariev I; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Sattler M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Nasser MW; Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Jain M; Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Batra SK; Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Soldi R; Applied Cancer Research and Drug Discovery Division, Translational Genomics Research Institute (TGen) of City of Hope, Phoenix, AZ 850043, USA.
  • Sharma S; Applied Cancer Research and Drug Discovery Division, Translational Genomics Research Institute (TGen) of City of Hope, Phoenix, AZ 850043, USA.
  • Fakih M; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
  • Mohanty SK; Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India.
  • Mainan A; Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India.
  • Wu X; Integrative Genomics Core, Beckman Research Institute, City of Hope, Monrovia, CA 91016, USA.
  • Chen Y; W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA.
  • He Y; W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA.
  • Chou TF; Proteome Exploration Laboratory, California Institute of Technology, Pasadena, CA 91125, USA.
  • Roy S; Department of Chemical Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, West Bengal 741246, India.
  • Orban J; W. M. Keck Laboratory for Structural Biology, University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, MD 20850, USA.
  • Kulkarni P; Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
  • Salgia R; Department of Medical Oncology and Experimental Therapeutics, City of Hope National Medical Center, Duarte, CA 91010, USA.
Sci Adv ; 9(41): eade3816, 2023 10 13.
Article in En | MEDLINE | ID: mdl-37831779
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 ß4 (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/ß-catenin signaling pathway. Thus, silencing both ITGB4 and ß-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 ß-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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Non-Small-Cell Lung / Drug Resistance, Neoplasm / Lung Neoplasms Limits: Humans Language: En Journal: Sci Adv Year: 2023 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Non-Small-Cell Lung / Drug Resistance, Neoplasm / Lung Neoplasms Limits: Humans Language: En Journal: Sci Adv Year: 2023 Document type: Article