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

Abstract

Purpose: In ALK-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. Experimental Design: We used integrated clinical and next-generation sequencing data generated in a nationwide lung cancer genome screening project (LC-SCRUM-Japan). ALK-rearranged NSCLC cell lines expressing wild-type or mutant TP53 were used to evaluate cellular apoptosis induced by ALK-TKIs. Results: In 90 patients with ALK-rearranged NSCLC who were treated with a selective ALK-TKI, alectinib, TP53 comutated patients showed significantly worse progression-free survival (PFS) than TP53 wild-type patients [median PFS, 11.7 months (95% confidence interval, CI, 6.3–not reached, NR) vs. NR (23.6–NR); P = 0.0008; HR, 0.33 (95% CI, 0.17–0.65)]. ALK-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 ALK-rearranged NSCLC cells with nonfunctional p53. Conclusions: These clinical and preclinical results indicate concomitant TP53 mutations reduce the efficacy of alectinib for ALK-rearranged NSCLC and the combined use of a proteasome inhibitor with alectinib is a promising therapy for ALK-rearranged/TP53-mutated NSCLC.

Going beneath the tip of the iceberg. Identifying and understanding EML4-ALK variants and TP53 mutations to optimize treatment of ALK fusion positive (ALK+) NSCLC

“…Additionally, OS was worse in patients with TP53 mutations (HR = 4.9) compared to patients with v3 (HR = 2.4), with an additive effect in double positive patients (HR = 9.1) [31]. This observation is also supported by Tanimoto and colleagues suggesting EML4-ALK v3 and TP53mt patients have the worst outcome [36]. Tanimoto also demonstrated that EML4-ALK v1 and TP53mt patients had a short PFS also but still better than EML4-ALK v3 and TP53mt patients (Table 3).…”

“…J o u r n a l P r e -p r o o f the presence of TP53 mutations is a poor prognostic factor for PFS and OS [48]. Overall, the presence of TP53 mutations conferred shorter PFS under most treatment conditions (chemotherapy, crizotinib, or next-generation ALK TKIs) (Table 3) [27,28,36,47,[50][51][52]. The clinicopathologic characteristics between TP53+ versus TP53-ALK+ NSCLC only differed by smoking status (79.6% never-smokers in TP53versus 46.7% in TP53+, p = 0.021), but there was no difference in sex (p = 0.559), age (p = 0.556), histology (p = 0.234), stage (p = 0.565), or performance status (p = 1.000) [52].…”

“…However, the distribution of the EML4-ALK variants among the TP53 mutations was not known but based on other studies, there was no difference among various EML4-ALK variants [52]. Recently, Tanimoto and colleagues have demonstrated that the addition of proteosome inhibitor to ALK TKIs can overcome TP53 mutations in vitro by enhancing the noxa interaction with Mcl-1 (an anti-apoptotic protein) leading to an alternate TP53-independent apoptosis [36].…”

“…Again, the most potent ALK TKI preclinically is lorlatinib and although we eagerly await updates from the CROWN study, we would recommend lorlatinib as the preferred first-line treatment of ALK+ NSCLC even in the presence of TP53 mutations. Upon progression from ALK TKI, the recent report by Tanimoto and colleagues indicated that proteosome inhibitors in concert with ALK TKI may be able to provide TP53-independent apoptosis to compensate for the loss of TP53-dependent apoptosis [36].…”

Primary resistance to alectinib in a patient with STRN‐ALK‐positive non‐small cell lung cancer: A case report

“…However, the mechanism of primary resistance to alectinib has been rarely reported. A preclinical study indicated ALK‐rearranged NSCLC cell lines concomitant with TP53 mutations were resistant to alectinib‐induced apoptosis 17 . Gainor et al analyzed repeat biopsies from post‐second‐generation ALK‐TKI treated patients, in whom TP53 mutations occurred most frequently 10 .…”