Targeting doublecortin-like kinase 1 reveals a novel strategy to circumvent chemoresistance and metastasis in ovarian cancer.

Autor: Dogra S; 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., Elayapillai SP; 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., Qu D; Department of Medicine, Section of Digestive Diseases and Nutrition, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Pitts K; Department of Medicine, Section of Digestive Diseases and Nutrition, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Filatenkov A; Peggy and Charles Stephenson Cancer Center, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Houchen CW; 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., Berry WL; Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA., Moxley K; Oklahoma Cancer Specialists and Research Institute, Tulsa, OK, USA., Hannafon BN; 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. Electronic address: bethany-hannafon@ouhsc.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2023 Dec 01; Vol. 578, pp. 216437. Date of Electronic Publication: 2023 Oct 12.
DOI: 10.1016/j.canlet.2023.216437
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: C·W.H. is an inventor on a patent for nanoparticle-encapsulated DCLK1-targeted siRNAs. C.W.H. is the co-founder of COARE Holdings, Inc. The remaining authors declare that they have no competing interests.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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