Abstract
BACKGROUND: KRAS(G12C) inhibitors have shown promising efficacy in early clinical trials, but drug resistance compromises their long-term benefits. Therefore, it is critical to understand the mechanisms of drug resistance and to design appropriate combinatory treatments to improve efficacy. METHODS: To understand the comprehensive mechanisms of drug resistance, we treated lung cancer cells with KRAS(G12C) inhibitors for different periods and performed transcriptional profiling and signaling analysis to identify critical factors and pathways that drive drug tolerance and resistance. We also evaluated several drug combinations in vitro and in vivo to identify potentially effective therapeutics. RESULTS: We found that the feedback activation of multiple receptor tyrosine kinases (RTKs) may have cooperatively induced intrinsic and adaptive resistance to KRAS(G12C) inhibitors. Notably, continuous KRAS inhibition induced a multidrug-resistant phenotype, implying that upfront combinatory treatment might be required to treat this group of patients. We also demonstrated that concurrently targeting multiple nodes in the RTK/RAS/RAF/MEK/ERK axis improved the efficacy of KRAS(G12C) inhibitors, mainly by suppressing the reactivation of the mitogen-activated protein kinase (MAPK) pathway. Moreover, the combined use of HSP90 and KRAS(G12C) inhibitors effectively induced tumor regression in lung adenocarcinoma models in vitro and in vivo. CONCLUSION: Together, our findings revealed mechanisms underlying KRAS(G12C) inhibitors resistance and provided novel candidate combinatory strategies to improve their anticancer activity.