Enhancing the Therapeutic Efficacy of KRASG12C Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90

Ying Liu; Lei Wu; Hong Lu; En Wu; Jun Ni; Xiaorong Zhou

doi:10.1155/2021/2721466

Enhancing the Therapeutic Efficacy of KRAS^G12C Inhibitors in Lung Adenocarcinoma Cell Models by Cotargeting the MAPK Pathway or HSP90

J Oncol. 2021 Nov 23:2021:2721466. doi: 10.1155/2021/2721466. eCollection 2021.

Authors

Ying Liu¹, Lei Wu¹, Hong Lu¹, En Wu^{1

2}, Jun Ni^{3

4}, Xiaorong Zhou¹

Affiliations

¹ Department of Immunology, Nantong University, School of Medicine, Nantong, Jiangsu 226001, China.
² Department of Physical Therapy, Shanghai Yangzhi Rehabilitation Hospital, Shanghai 201619, China.
³ Department of Rehabilitation, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, China.
⁴ Department of Rehabilitation, The Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China.

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.