SHP2 Contributes to Resistance of KRAS p.G12C-Driven Lung Cancer Cells to MRTX849 by Regulating β-catenin/c-MYC Axis.

SHP2 has been promulgated to be involved in chemoresistance in a variety of cancers. However, its relationship with MRTX849-resistance in KRAS G12C mutant lung cancer has not been revealed. Lung cancer cell lines resistant to MRTX849 were first constructed by repeated dosing over 10 months, and the parental and drug-resistant strains were evaluated for SHP2 expression at different time points (2, 4, 6, 8, 10 months). We further analyzed whether SHP2 knockdown affects the sensitivity of MRTX849-resistant cells to MRTX849, and overexpression of SHP2 in the parental cell line to assess its effect on MRTX849 resistance, mainly by CCK-8, clonogenic assay, TUNEL staining and Western blotting to assess cell viability, proliferation, apoptosis, as well as β-catenin/c-MYC pathway protein expression. SHP2 expression remained largely unchanged in the parental cell line, whereas they were gradually upregulated in a time-dependent manner in the resistant cell line. SHP2 knockdown enhanced the sensitivity of MRTX849-resistant cell lines to MRTX849 and encouraged the killing of lung cancer cells by MRTX849, as indicated by a more significant decrease in cell viability and proliferation after knockdown of SHP2 in the presence of MRTX849 compared with MRTX849 untreated, while apoptosis was more significantly enhanced. Additionally, SHP2 overexpression enhanced the resistance of MRTX849 to lung cancer cells. Eventually, we confirmed that the MRTX849-resistance effect of SHP2 on lung cancer cells was through the activation of the β-catenin/c-MYC pathway. SHP2 contributes to resistance of KRAS G12C-driven lung cancer cells to MRTX849 by regulating β-catenin/c-MYC axis.

Informations de copyright

© 2023 by the Association of Clinical Scientists, Inc.