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Ref Type Journal Article
PMID (33310890)
Authors Tanimoto A, Matsumoto S, Takeuchi S, Arai S, Fukuda K, Nishiyama A, Yoh K, Ikeda T, Furuya N, Nishino K, Ohe Y, Goto K, Yano S
Title Proteasome Inhibition Overcomes ALK-TKI Resistance in ALK-Rearranged/TP53-Mutant NSCLC via Noxa Expression.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 27
Issue 5
Date 2021 Mar 01
URL
Abstract Text 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.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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK TP53 Q331* lung non-small cell carcinoma resistant Alectinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells harboring EML4-ALK and TP53 Q331* were resistant to treatment with Alecensa (alectinib) in culture (PMID: 33310890). 33310890
EML4 - ALK TP53 V274fs lung non-small cell carcinoma sensitive Alectinib + Ixazomib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination therapy of Alecensa (alectinib) and Ninlaro (ixazomib) inhibited the proliferation of non-small cell lung cancer cells harboring EML4-ALK and TP53 Q331* in culture and resulted in tumor regression in cell line xenograft models, with 3/8 achieving complete tumor regression (PMID: 33310890). 33310890
EML4 - ALK TP53 Q331* lung non-small cell carcinoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells harboring EML4-ALK and TP53 Q331* were resistant to treatment with Xalkori (crizotinib) in culture (PMID: 33310890). 33310890
EML4 - ALK TP53 Q331* lung non-small cell carcinoma sensitive Alectinib + Ixazomib Preclinical - Cell culture Actionable In a preclinical study, the combination therapy of Alecensa (alectinib) and Ninlaro (ixazomib) inhibited the proliferation of non-small cell lung cancer cells harboring EML4-ALK and TP53 Q331* in culture (PMID: 33310890). 33310890
EML4 - ALK TP53 V274fs lung non-small cell carcinoma resistant Crizotinib Preclinical - Cell culture Actionable In a preclinical study, non-small cell lung cancer cells harboring EML4-ALK and TP53 V274fs were resistant to treatment with Xalkori (crizotinib) in culture (PMID: 33310890). 33310890
EML4 - ALK TP53 V274fs lung non-small cell carcinoma resistant Alectinib Preclinical - Cell line xenograft Actionable In a preclinical study, non-small cell lung cancer cells harboring EML4-ALK and TP53 V274* were resistant to treatment with Alecensa (alectinib), demonstrating cell growth in culture and tumor growth in cell line xenograft models (PMID: 33310890). 33310890