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- Title
GSK3 inhibition circumvents and overcomes acquired lorlatinib resistance in ALK-rearranged non-small-cell lung cancer.
- Authors
Shimizu, Yuki; Okada, Koutaroh; Adachi, Jun; Abe, Yuichi; Narumi, Ryohei; Uchibori, Ken; Yanagitani, Noriko; Koike, Sumie; Takagi, Satoshi; Nishio, Makoto; Fujita, Naoya; Katayama, Ryohei
- Abstract
Anaplastic lymphoma kinase (ALK) fusion is found in ~3%–5% of patients with non-small-cell lung cancers (NSCLCs). Although the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib shows high clinical efficacy in ALK-positive NSCLC, most of the patients eventually relapse with acquired resistance. Recently, drug-tolerant persister (DTP) cells have been considered an important seed of acquired resistance cells. In this study, we established lorlatinib intermediate resistant cells from a patient-derived cell model. Glycogen synthase kinase 3 (GSK3) inhibitions significantly suppressed lorlatinib intermediate resistant cell growth. GSK3 inhibition also sensitized acquired resistance cells derived from alectinib-treated patients with or without secondary mutations to lorlatinib. Therefore, GSK3 plays a crucial role in developing acquired resistance against lorlatinib in ALK-positive NSCLC mediated by lorlatinib intermediate resistant cells and could be a potential molecular target to prevent acquired lorlatinib resistance and overcome ALK-TKI resistance.
- Subjects
NON-small-cell lung carcinoma; GLYCOGEN synthase kinase; ANAPLASTIC lymphoma kinase; PROTEIN-tyrosine kinase inhibitors; DRUG target
- Publication
NPJ Precision Oncology, 2022, Vol 6, Issue 1, p1
- ISSN
2397-768X
- Publication type
Article
- DOI
10.1038/s41698-022-00260-0