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 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.