ABT-737, a BH3 mimetic, circumvents JNK-mediated upregulation of anti-apoptotic molecules in cisplatin-treated non-small cell lung cancer

Abstract

A subset of non-small cell lung cancers (NSCLC), which do not have a druggable driver oncogene, are treated with cytotoxic chemotherapy, most commonly cisplatin, but clinical outcome is suboptimal. Tumors develop multiple resistance mechanisms and elevated levels of anti-apoptotic proteins triggered by a cisplatin-induced DNA damage response correlate with resistance. Here, we investigated the synergistic effects of a co-treatment with cisplatin and a BH3 mimetic, ABT-737, in both cell culture and in vivo NSCLC models. In A549 and H460 cells, there was a dose-dependent phosphorylation of Jun N-terminal kinase (JNK) by cisplatin treatment, followed by increased expression of anti-apoptotic molecules. Anisomycin, a JNK-specific activator, increased the mRNA levels of anti-apoptotic molecules and SP600125, JNK-inhibitor, suppressed their expression, suggesting that the elevation of the anti-apoptotic molecules was mediated by JNK. ABT-737 displaced BCL-xL from mitochondria to the cytoplasm and induced oligomerization of BAK. Furthermore, ABT-737 released cytochrome c from mitochondria. ABT-737 itself showed cytotoxic effects and a combination of ABT-737 with cisplatin showed strong synergistic cytotoxicity. In a Lox-Stop-Lox (LSL) K-ras G12D mouse model, co-treatment with ABT-737 and cisplatin induced significant tumor regression. These findings reveal a synergistic cytotoxic and anti-tumor activity of ABT-737 and cisplatin co-treatment in a preclinical model, and suggest that clinical trials using this strategy may be beneficial in advanced NSCLC patients.