Proteasome Inhibition Overcomes ALK-TKI Resistance in <i>ALK</i>-Rearranged/<i>TP53</i>-Mutant NSCLC via Noxa Expression.

Abstract

In <i>ALK</i>-rearranged non-small cell lung cancer (NSCLC), impacts of concomitant genetic alterations on targeted therapies with ALK-tyrosine kinase inhibitors (ALK-TKI) are not yet well understood. Here, we investigated genetic alterations related to ALK-TKI resistance using clinico-genomic data and explored effective therapies to overcome the resistance in preclinical models through the identification of underlying molecular mechanisms. We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). <i>ALK</i>-rearranged NSCLC cell lines expressing wild-type or mutant <i>TP53</i> were used to evaluate cellular apoptosis induced by ALK-TKIs. In 90 patients with <i>ALK</i>-rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, <i>TP53</i> comutated patients showed significantly worse progression-free survival (PFS) than <i>TP53</i> wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3-not reached, NR) vs. NR (23.6-NR); <i>P</i> = 0.0008; HR, 0.33 (95% CI, 0.17-0.65)]. <i>ALK</i>-rearranged NSCLC cell lines that lost p53 function were resistant to alectinib-induced apoptosis, but a proteasome inhibitior, ixazomib, markedly induced apoptosis in the alectinib-treated cells by increasing the expression of a proapoptotic protein, Noxa, which bound to an antiapoptotic protein, Mcl-1. In subcutaneous tumor models, combination of ixazomib and alectinib prominently induced tumor regression and apoptosis even though the tumors were generated from <i>ALK</i>-rearranged NSCLC cells with nonfunctional p53. These clinical and preclinical results indicate concomitant <i>TP53</i> mutations reduce the efficacy of alectinib for <i>ALK</i>-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for <i>ALK</i>-rearranged/<i>TP53</i>-mutated NSCLC.