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

Activating mutations in the KRAS gene are among the most significant genomic alterations driving the tumorigenesis of non-small cell lung cancer (NSCLC). As of now, the treatment of KRAS-mutant NSCLC remains a critical unmet medical need. We evaluated the in vivo treatment responses of 13 KRAS-mutant and 14 KRAS wild-type NSCLC patient-derived xenografts (PDXs) to several agents targeting established NSCLC vulnerabilities, including the MEK inhibitor trametinib, the MDM2 inhibitor KRT-232, and the BCL-XL/BCL-2 inhibitor navitoclax.

The findings indicated that the tumor regression rates after single-agent therapy with KRT-232, trametinib, and navitoclax were 11%, 10%, and 0%, respectively. However, combining trametinib with KRT-232 or navitoclax enhanced partial response rates compared to single-agent treatment in some PDX models. Specifically, tumor regression was observed in 23% and 50% of PDXs treated with trametinib plus KRT-232 and trametinib plus navitoclax, respectively. Additionally, the disease control rates in KRAS-mutant PDXs were 90%-100% following treatment with either combination.

A correlation analysis of treatment responses with genomic and proteomic biomarkers showed a significant association between sensitivity to KRT-232 and the presence of TP53 wild-type or STK11 mutant genotypes (P<0.05). Furthermore, the levels of several proteins, such as GSK3b, Nrf2, LKB1/pS334, and SMYD3, were notably linked with sensitivity to the trametinib plus navitoclax combination.

In summary, the combination of trametinib with either KRT-232 or navitoclax demonstrated improved efficacy compared to each agent alone in a subset of NSCLC PDX models with KRAS mutations. These results suggest that expanded clinical trials of these targeted drug combinations in NSCLC are justified.