KRT-232 and navitoclax enhance trametinib's anti-Cancer activity in non-small cell lung cancer patient-derived xenografts with KRAS mutations.

Abstract

Activating mutations of the KRAS gene are one of the major genomic alterations associated with tumorigenesis of non-small cell lung cancer (NSCLC). Thus far, treatment of KRAS-mutant NSCLC remains an unmet medical need. We determined the in vivo treatment responses of 13 KRAS mutant and 14 KRAS wild type NSCLC patient-derived xenografts (PDXs) to agents that target known NSCLC vulnerabilities: the MEK inhibitor trametinib, the MDM2 inhibitor KRT-232, and the BCL-XL/BCL-2 inhibitor navitoclax. The results showed that the tumor regression rate after single agent therapy with KRT-232, trametinib and navitoclax was 11%, 10% and 0%, respectively. Combination therapies of trametinib plus KRT-232 and trametinib plus navitoclax led to improved partial response rates over single-agent activity in a subset of PDX models. Tumor regression was observed in 23% and 50% of PDXs after treatment with trametinib plus KRT-232 and trametinib plus navitoclax, respectively. The disease control rates in KRAS-mutant PDXs tested were 90%-100% after treatment with trametinib plus KRT-232 or plus navitoclax. A correlation analysis of treatment responses and genomic and proteomic biomarkers revealed that sensitivity to KRT-232 was significantly associated with TP53 wild-type or STK11 mutant genotypes (P<0.05). The levels of several proteins, including GSK3b, Nrf2, LKB1/pS334, and SMYD3, were significantly associated with sensitivity to trametinib plus navitoclax. Thus, the combination of trametinib plus KRT-232 or navitoclax resulted in improved efficacy compared with the agents alone in a subgroup of NSCLC PDX model with KRAS mutations. Expanded clinical trials of these targeted drug combinations in NSCLC are warranted.

• Authors: Xiaoshan Zhang, Ran Zhang, Huiqin Chen, Li Wang, Chenghui Ren, Apar Pataer, Shuhong Wu, Qing H Meng, Min Jin Ha, Jeffrey Morris, Yuanxin Xi, Jing Wang, Jianhua Zhang, Don L Gibbons, John V Heymach, Funda Meric-Bernstam, John Minna, Stephen G Swisher, Jack A Roth, Bingliang Fang
• Journal: American journal of cancer research (Am J Cancer Res) Vol. 10 Issue 12 Pg. 4464-4475 ( 2020) ISSN: 2156-6976 [Print] United States
• PMID: 33415011 (Publication Type: Journal Article)
• Copyright: AJCR Copyright © 2020.