ANP32A-mediated Histone 3 K27 Acetylation is Essential for the response of KRAS-mutant Non-Small Cell Lung Cancer to Sotorasib

Objective: Drug resistance is a major challenge for the target therapy of KRAS-mutant non-small cell lung cancer (NSCLC). This study aims to identify key regulators and biomarkers for the development of new combination treatment to improve the target therapy.Methods: The clinical relevance of ANP32A with KRAS-mutant NSCLC was investigated. ANP32A function in KRAS-mutant NSCLC and Sotorasib resistance were tested by measuring proliferation, migration, invasion, cell cycle profile and apoptosis in ANP32A-deficient cells. Co-immunoprecipitation, chromatin immunoprecipitation, immunofluorescence, and analyses on histone acetylation and transcriptomic profile were performed to identify ANP32A patterner and probe the underlying mechanisms. The therapeutic effect of ANP32A-mediated histone acetylation and inhibition of histone deacetyltransferase (HDAC) by Tricostatin A (TSA) on Sotorasib therapy was verified in vitro and in vivo.