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

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

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

Am J Cancer Res. 2020 Dec 1;10(12):4464-4475. eCollection 2020.

Authors

Xiaoshan Zhang¹, Ran Zhang¹, Huiqin Chen², Li Wang¹, Chenghui Ren¹, Apar Pataer¹, Shuhong Wu¹, Qing H Meng³, Min Jin Ha², Jeffrey Morris², Yuanxin Xi⁴, Jing Wang⁴, Jianhua Zhang⁵, Don L Gibbons⁶, John V Heymach⁶, Funda Meric-Bernstam⁷, John Minna⁸, Stephen G Swisher¹, Jack A Roth¹, Bingliang Fang¹

Affiliations

¹ Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.
² Department of Biostatistics, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.
³ Department of Laboratory Medicine, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.
⁴ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.
⁵ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.
⁶ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.
⁷ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.
⁸ Hamon Center for Therapeutic Oncology, The Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center Dallas, Texas, USA.

PMID: 33415011
PMCID: PMC7783771

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-X_L/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.

Keywords: Bcl2; MDM2; MEK; NSCLC; combination therapy; target therapy.

Abstract

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