Department of Surgery, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
Department of Surgery, Thyroid Cancer Center, Gangnam Severance Hospital, Institute of Refractory Thyroid Cancer, Yonsei University College of Medicine, Seoul 06273, Republic of Korea.
Int J Mol Sci. 2024 Oct 3;25(19):10646. 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.
甲状腺乳头状癌（PTC）是最可治愈的癌症之一，许多病例可完全治愈。然而，抗癌药物的耐药性常常导致转移或复发，导致癌症治疗失败，并最终导致患者死亡。转移性或复发性 PTC 患者分子差异的机制，特别是通过表观遗传重编程对抗癌药物耐药的机制，仍知之甚少。因此，难治性 PTC 是一个重大挑战，迫切需要有效的治疗策略。因此，本研究旨在寻找小分子抑制剂来增强对 lenvatinib 耐药性 PTC 的治疗效果。我们观察到与 lenvatinib 敏感的细胞相比，来源于患者的 lenvatinib 耐药性 PTC 细胞中的肌浆/内质网钙 ATP 酶（SERCA）水平升高，表明其可能成为治疗靶点。随后，我们通过计算机筛选鉴定出两种 SERCA 抑制剂[候选物 40（异氟烷）和 42（乙叉二膦酸）]。这些候选物在异种移植肿瘤模型中显示出显著的肿瘤缩小作用，并在与 lenvatinib 联合使用时降低患者来源的 lenvatinib 耐药性 PTC 细胞的细胞活力。我们的研究结果为开发新的联合治疗方法以有效靶向高度恶性、抗癌药物耐药性癌症具有潜在的临床价值。
