Department of Obstetrics and Gynecology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Department of Medicine, Section of Digestive Diseases and Nutrition, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Cancer Lett. 2023 Dec 1;578:216437. doi: 10.1016/j.canlet.2023.216437. Epub 2023 Oct 12.
Ovarian cancer (OvCa) has a dismal prognosis because of its late-stage diagnosis and the emergence of chemoresistance. Doublecortin-like kinase 1 (DCLK1) is a serine/threonine kinase known to regulate cancer cell "stemness", epithelial-mesenchymal transition (EMT), and drug resistance. Here we show that DCLK1 is a druggable target that promotes chemoresistance and tumor progression of high-grade serous OvCa (HGSOC). Importantly, high DCLK1 expression significantly correlates with poor overall and progression-free survival in OvCa patients treated with platinum chemotherapy. DCLK1 expression was elevated in a subset of HGSOC cell lines in adherent (2D) and spheroid (3D) cultures, and the expression was further increased in cisplatin-resistant (CPR) spheroids relative to their sensitive controls. Using cisplatin-sensitive and resistant isogenic cell lines, pharmacologic inhibition (DCLK1-IN-1), and genetic manipulation, we demonstrate that DCLK1 inhibition was effective at re-sensitizing cells to cisplatin, reducing cell proliferation, migration, and invasion. Using kinase domain mutants, we demonstrate that DCLK1 kinase activity is critical for mediating CPR. The combination of cisplatin and DCLK1-IN-1 showed a synergistic cytotoxic effect against OvCa cells in 3D conditions. Targeted gene expression profiling revealed that DCLK1 inhibition in CPR OvCa spheroids significantly reduced TGFβ signaling, and EMT. We show in vivo efficacy of combined DCLK1 inhibition and cisplatin in significantly reducing tumor metastases. Our study shows that DCLK1 is a relevant target in OvCa and combined targeting of DCLK1 in combination with existing chemotherapy could be a novel therapeutic approach to overcome resistance and prevent OvCa recurrence.
卵巢癌（OvCa）由于其晚期诊断和化疗耐药的出现，预后较差。双皮质激酶 1（DCLK1）是一种丝氨酸/苏氨酸激酶，已知可调节癌细胞“干性”、上皮-间充质转化（EMT）和耐药性。在这里，我们表明 DCLK1 是一个可靶向的靶点，可促进高级别浆液性卵巢癌（HGSOC）的化疗耐药和肿瘤进展。重要的是，DCLK1 表达水平高与接受铂类化疗的卵巢癌患者的总生存期和无进展生存期显著相关。在贴壁（2D）和球体（3D）培养物中，DCLK1 在一组 HGSOC 细胞系中表达上调，并且在顺铂耐药（CPR）球体中相对于其敏感对照物表达进一步增加。使用顺铂敏感和耐药的同基因细胞系、药物抑制（DCLK1-IN-1）和遗传操作，我们证明 DCLK1 抑制可有效使细胞重新对顺铂敏感，减少细胞增殖、迁移和侵袭。使用激酶结构域突变体，我们证明 DCLK1 激酶活性对于介导 CPR 至关重要。在 3D 条件下，顺铂和 DCLK1-IN-1 的联合使用显示出对 OvCa 细胞的协同细胞毒性作用。靶向基因表达谱分析表明，DCLK1 抑制在 CPR OvCa 球体中显著降低了 TGFβ 信号和 EMT。我们在体内证明了 DCLK1 抑制与顺铂联合使用可显著减少肿瘤转移的疗效。我们的研究表明 DCLK1 是 OvCa 中的一个相关靶点，联合靶向 DCLK1 与现有化疗相结合可能是克服耐药性和预防 OvCa 复发的一种新的治疗方法。
