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

• DOI: 10.1126/sciadv.ade3816
• Publication Date: 2023-10-13T17:58:24Z
• Authors: Atish Mohanty; Arin Nam; Saumya Srivastava; Jeff Jones; Brett Lomenick; Sharad S. Singhal; Linlin Guo; Hyejin Cho; Aimin Li; Amita Behal; Tamara Mirzapoiazova; Erminia Massarelli; Marianna Koczywas; Leonidas D. Arvan...; Tonya Walser; Victoria Villaflor; Stanley Hamilton; Isa Mambetsariev; Martin Sattler; Mohd W. Nasser; Maneesh Jain; Surinder K. Batra; Raffaella Soldi; Sunil Sharma; Marwan Fakih; Saswat Kumar Mohanty; Avijit Mainan; Xiwei Wu; Yihong Chen; Yanan He; Tsui-Fen Chou; Susmita Roy; John Orban; Prakash Kulkarni; Ravi Salgia
• Keywords: Proto-Oncogene Proteins p21(ras); Multidisciplinary; Lung Neoplasms; Drug Resistance, Neoplasm; Carcinoma, Non-Small-Cell Lung; Mutation; 610; Humans; 600; Biomedicine and Life Sciences; Antiviral Agents; beta Catenin; 3. Good health

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