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Acquired resistance to tyrosine kinase inhibitors (TKIs), such as osimertinib, poses a major barrier to effective treatment of nonsmall cell lung cancer (NSCLC). Recent data suggest that lysosomal Ca2+ signaling, particularly via transient receptor potential mucolipin 3 (TRPML3; also known as MCOLN3), contributes to TKI resistance by promoting lysosomal exocytosis and drug efflux.

Here, we investigated the regulatory role of microRNA-601 (miR-601) in modulating TRPML3 expression and its impact on osimertinib resistance in NSCLC. Bioinformatic predictions using the DIANA microT-CDS algorithm identified TRPML3 as a putative target of miR-601. Luciferase reporter assays confirmed direct binding of miR-601 to the TRPML3 3′-untranslated region. Functional assays were conducted with parental and osimertinib-resistant PC9 and HCC827 cells to evaluate the effects of miR-601 on TRPML3 expression, apoptosis, cell-cycle progression, and drug sensitivity. Osimertinib treatment led to a time-dependent miR- 601 downregulation in NSCLC cells, and its basal expression remained suppressed in resistant sublines. miR-601 overexpression reduced TRPML3 protein levels, enhanced poly(ADP-ribose) polymerase cleavage, induced G0/G1 cell-cycle arrest, and restored osimertinib sensitivity. Similar effects were observed upon TRPML3 knockdown, supporting a TRPML3-dependent mechanism.

Thus, miR-601 negatively regulates TRPML3 and modulated TKI responses in NSCLC cells. Restoring miR-601 expression may represent a promising therapeutic strategy for overcoming acquired osimertinib resistance by targeting TRPML3-mediated lysosomal signaling.

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기사명 저자명 페이지 원문 목차
(A) qualitative study of staff and provider experiences with follow-up colonoscopy in a community health center and gastroenterology specialty Cynthia M. Mojica, Jennifer L. Schneider, Jamie H. Thompson, Gloria D. Coronado p. 185-195
Sex disparity in cancer and non-cancer mortality among Korean cancer survivors Ansun Jeong, Soyeoun Kim, Somin Jeon, Boyoung Park p. 196-204
MicroRNA-601 enhances osimertinib sensitivity by targeting transient receptor potential mucolipin 3 in non-small cell lung cancer cells Mi Seong Kim, Min Seuk Kim p. 205-211

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