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A small-molecule degrader selectively inhibits the growth of ALK-rearranged lung cancer with ceritinib resistance.

ABSTRACT: Anaplastic lymphoma kinase (ALK) is a highly responsive therapeutic target for ALK-rearranged non-small cell lung cancer (NSCLC). However, patients with this cancer invariably relapse because of the development of ALK inhibitor resistance resulting from mutations within the ALK tyrosine kinase domain. Herein, we report the discovery of dEALK1, a small-molecule degrader of EML4-ALK fusion proteins, with capability of overcoming resistance to ALK inhibitor ceritinib. dEALK1 induces rapid and selective degradation of wild-type (WT) EML4-ALK and mutated EML4-ALKs acquiring resistance to ceritinib, leading to inhibition of cell proliferation and increase of apoptosis in NSCLC cells expressing WT EML4-ALK or ceritinib-resistant EML4-ALK mutants in vitro. Furthermore, dEALK1 also exerts a potent antitumor activity against EML4-ALK-positive xenograft tumors without or with harboring ceritinib-resistant EML4-ALK mutations in vivo. Our study suggests that dEALK1-induced degradation of EML4-ALK fusion proteins is a promising therapeutic strategy for treatment of ALK-rearranged lung cancer with ceritinib resistance.

SUBMITTER: Li X

PROVIDER: S-EPMC10847737 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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A small-molecule degrader selectively inhibits the growth of <i>ALK</i>-rearranged lung cancer with ceritinib resistance.

Li Xin X Wang Zixiong Z Chen Chao C Yang Fan F Liu Ping P Fang Shu S Wang Bin B Chen Shi S Li Xinjian X

iScience 20240126 2

Anaplastic lymphoma kinase (ALK) is a highly responsive therapeutic target for <i>ALK</i>-rearranged non-small cell lung cancer (NSCLC). However, patients with this cancer invariably relapse because of the development of ALK inhibitor resistance resulting from mutations within the ALK tyrosine kinase domain. Herein, we report the discovery of dEALK1, a small-molecule degrader of EML4-ALK fusion proteins, with capability of overcoming resistance to ALK inhibitor ceritinib. dEALK1 induces rapid an ...[more]

PMID: 38327793

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Project description:BackgroundNon-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.MethodsIn this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.ResultsA total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).ConclusionsCeritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

Dataset Information

A small-molecule degrader selectively inhibits the growth of ALK-rearranged lung cancer with ceritinib resistance.

Publications

A small-molecule degrader selectively inhibits the growth of <i>ALK</i>-rearranged lung cancer with ceritinib resistance.

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