TRPML3‑mediated lysosomal Ca<sup>2+</sup> release enhances drug sequestration and biogenesis, promoting osimertinib resistance in non‑small cell lung cancer

Kim,Mi Seong; Kim,Min Seuk

doi:10.3892/or.2025.8946

TRPML3‑mediated lysosomal Ca²⁺ release enhances drug sequestration and biogenesis, promoting osimertinib resistance in non‑small cell lung cancer

Authors:
- Mi Seong Kim
- Min Seuk Kim
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Affiliations: Department of Oral Physiology, Institute of Biomaterial‑Implant, School of Dentistry, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
Published online on: July 14, 2025 https://doi.org/10.3892/or.2025.8946
Article Number: 113
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lysosomes and lysosomal Ca²⁺ play crucial roles in cellular homeostasis and drug resistance. The lysosomal Ca²⁺ channel transient receptor potential mucolipin 3 (TRPML3; also known as mucolipin‑3 or MCOLN3) is a key regulator of autophagy and membrane trafficking; however, its role in tyrosine kinase inhibitor (TKI) resistance remains unclear. The contribution of TRPML3 to osimertinib resistance in non‑small cell lung cancer (NSCLC) was therefore assessed. Using publicly available RNA sequencing data, including profiles from clinical samples before and after osimertinib treatment, TRPML3 expression was measured in lung adenocarcinoma (LUAD) tissues. Additionally, two‑dimensional cell culture of, and three‑dimensional spheroids derived from, NSCLC cell lines were used to elucidate roles of TRPML3 in drug resistance. TRPML3 expression was significantly upregulated in both LUAD tissues from patients with residual disease after osimertinib treatment, as well as in osimertinib‑resistant NSCLC cells. TRPML3 knockdown in resistant PC9 cells restored sensitivity to osimertinib and multiple TKIs; this was replicated in spheroid models. Mechanistically, osimertinib induced intracellular Ca²⁺ oscillations in PC9 cells via lysosomal Ca²⁺ release through TRPML3 rather than through TRPML1. In summary, the present findings suggest that elevated TRPML3 expression compensates for TRPML1 to maintain lysosomal acidity and biogenesis during TKI treatment, facilitating drug sequestration and resistance and identifying TRPML3 as a potential target for overcoming osimertinib resistance in NSCLC.

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