New Small-Molecule SERCA Inhibitors Enhance Treatment Efficacy in Lenvatinib-Resistant Papillary Thyroid Cancer

• Published in: International journal of molecular sciences 2024-10, Vol.25 (19), p.10646
• Main Authors: Kim, Jungmin, Chang, Hang-Seok, Yun, Hyeok Jun, Chang, Ho-Jin, Park, Ki Cheong
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Candidates; Cell Line, Tumor; Cell Proliferation - drug effects; Cells; Chemical compounds; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug therapy; Drug therapy, Combination; drug-resistant; Endoplasmic reticulum; Enzyme inhibitors; Epigenetics; Female; Fibroblasts; Gene expression; Growth factors; Health aspects; Homeostasis; Humans; lenvatinib; Medical prognosis; Metastasis; Mice; Mice, Nude; papillary thyroid cancer; Patients; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; Physiological aspects; Potassium; Quinolines - pharmacology; Quinolines - therapeutic use; Sarcoplasmic Reticulum Calcium-Transporting ATPases - antagonists & inhibitors; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; SERCA inhibitors; Thyroid cancer; Thyroid Cancer, Papillary - drug therapy; Thyroid Cancer, Papillary - pathology; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - pathology; Transcription factors; Xenograft Model Antitumor Assays
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms251910646

Papillary thyroid cancer (PTC) is one of the most treatable forms of cancer, with many cases being fully curable. However, resistance to anticancer drugs often leads to metastasis or recurrence, contributing to the failure of cancer therapy and, ultimately, patient mortality. The mechanisms underlying molecular differences in patients with metastatic or recurrent PTC, particularly those resistant to anticancer drugs through epigenetic reprogramming, remain poorly understood. Consequently, refractory PTC presents a critical challenge, and effective therapeutic strategies are urgently needed. Therefore, this study aimed to identify small-molecule inhibitors to enhance treatment efficacy in lenvatinib-resistant PTC. We observed an increase in sarco/endoplasmic reticulum calcium ATPase (SERCA) levels in patient-derived lenvatinib-resistant PTC cells compared with lenvatinib-sensitive ones, highlighting its potential as a therapeutic target. We subsequently identified two SERCA inhibitors [candidates 40 (isoflurane) and 42 (ethacrynic acid)] through in silico screening. These candidates demonstrated significant tumor shrinkage in a xenograft tumor model and reduced cell viability in patient-derived lenvatinib-resistant PTC cells when used in combination with lenvatinib. Our findings have potential clinical value for the development of new combination therapies to effectively target highly malignant, anticancer drug-resistant cancers.