Abstract 557: Novel targeted combination therapies active in KRAS mutant non-small cell lung cancer (NSCLC) identified using patient-derived xenografts (PDX)
Authors: Zhang Xiaoshan , Zhang Ran , Chen Huiqin , Wang Li , Ren Chenghui , Wu Shuhong , Ha Min Jin , Morris Jeffrey , Xi Yuanxin , Wang Jing , Gibbons Don L. , Heymach John V. , Meric-Bernstam Funda , Minna John , Swisher Stephen G. , Roth Jack A. , Fang Bingliang 
Published: September 2020

Abstract
PDXs recapitulate histologic features, gene expression patterns, and genomic alterations in human primary tumors, and thus have emerged as robust preclinical models for drug development, molecular characterization of cancers, identification of biomarkers, and strategic development of precision therapy. We tested multiple combinations of small molecule targeted drugs selected on the basis of known NSCLC vulnerabilities for efficacy in NSCLC PDXs with known genotypes. We determined in vivo treatment responses to single agent and combination therapies for pathway targeted therapeutic agents, including the MEK inhibitor trametinib, the MDM2 inhibitor KRT-232, the BCL2/BCL-XL inhibitor navitoclax, and their combinations in 8-23 molecularly annotated NSCLC PDX models. Mice (n=3-5/group) were enrolled into treatment individually when tumors reached 200 mm3 in size, and were treated 5 days/week for 3 weeks. Tumor growth was monitored 2-3 times/week. We used the following criteria to determine treatment responses: 1) Tumor Regression (or partial response): tumor regression ≥ -30% based on tumor volume changes calculated by AUC0-21day or at day 21 after treatment start when compared with baseline (beginning of treatment at day 0); 2) Tumor Growth Inhibition (or stable disease): Tumor growth was significantly suppressed when compared with control (P &lt; 0.05), but no tumor regression was observed, or tumor regression was less than -30% based on tumor volume changes calculated by AUC0-21day or at day 21 after treatment start when compared with baseline; 3) Resistance: Tumor volume changes calculated by AUC0-21day was not significantly different from control group (P&gt;0.05). Our results showed that KRT-232 alone resulted in 15.8% (3/19) tumor regression and 26.3% (5/19) tumor growth inhibition, all in TP53 wild type PDXs. Trametinib alone induced 10% (2/20) tumor regression and 50% (10/20) growth inhibition, respectively. 80% (8/10) of KRAS mutant PDXs responded to trametinib treatment with tumor regression (1/10) or growth inhibition (7/10). Combination therapies of trametinib plus KRT-232 and trametinib plus navitoclax led to improved in vivo anticancer activity over single agent activity in a subset PDX models with KRAS mutations. Tumor regression was observed in 26% (6/23) and 50% (5/10) of trametinib plus KRT-232 and trametinib plus navitoclax treatment groups, respectively. Navitoclax alone did not induce tumor regression in 8 PDX models tested, and navitoclax plus KRT-232 did not lead to significant improvement in activity over single agents in 11 PDXs. Our results show that combination therapies of trametinib plus KRT-232 or navitoclax result in improved efficacy in a subgroup of NSCLC PDX models with KRAS mutations. Clinical trials with these targeted drug combinations in NSCLC are warranted.
Citation Format: Xiaoshan Zhang, Ran Zhang, Huiqin Chen, Li Wang, Chenghui Ren, Shuhong Wu, Min Jin Ha, Jeffrey Morris, Yuanxin Xi, Jing Wang, Don L. Gibbons, John V. Heymach, Funda Meric-Bernstam, John Minna, Stephen G. Swisher, Jack A. Roth, Bingliang Fang. Novel targeted combination therapies active in KRAS mutant non-small cell lung cancer (NSCLC) identified using patient-derived xenografts (PDX) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 557.