Onvansertib treatment overcomes olaparib resistance in high-grade ovarian carcinomas.

Autor: Chiappa M; Laboratory of Preclinical Gynecological Oncology, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Decio A; Laboratory of Cancer Metastasis Therapeutics, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Guarrera L; Computational Oncology Unit, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Mengoli I; Laboratory of Preclinical Gynecological Oncology, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Karki A; R&D Department, Cardiff Oncology, San Diego, CA, USA., Yemane D; R&D Department, Cardiff Oncology, San Diego, CA, USA., Ghilardi C; Laboratory of Cancer Metastasis Therapeutics, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Scanziani E; Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi Campus, Italy.; Mouse and Animal Pathology Lab (MAPLab), UniMi Foundation, Milan, Italy., Canesi S; Department of Veterinary Medicine and Animal Sciences (DIVAS), University of Milan, Lodi Campus, Italy.; Mouse and Animal Pathology Lab (MAPLab), UniMi Foundation, Milan, Italy., Barbera MC; Computational Oncology Unit, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Craparotta I; Computational Oncology Unit, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Bolis M; Computational Oncology Unit, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy., Fruscio R; Clinic of Obstetrics and Gynecology, Department of Medicine and Surgery, San Gerardo Hospital, University of Milan Bicocca, Monza, Italy., Grasselli C; Immuno-Pharmacology Unit, Department of Oncology, Mario Negri Institute for Pharmacological Research (IRCCS), Milan, Italy., Ceruti T; Laboratory of Laboratory of Cancer Pharmacology, Experimental Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy., Zucchetti M; Laboratory of Laboratory of Cancer Pharmacology, Experimental Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy., Patterson JC; Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Lu RA; Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Yaffe MB; Center for Precision Cancer Medicine, David H. Koch Institute for Integrative Cancer Research, Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA., Ridinger M; R&D Department, Cardiff Oncology, San Diego, CA, USA., Damia G; Laboratory of Preclinical Gynecological Oncology, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. giovanna.damia@marionegri.it., Guffanti F; Laboratory of Preclinical Gynecological Oncology, Experimental Oncology Department, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Jul 22; Vol. 15 (7), pp. 521. Date of Electronic Publication: 2024 Jul 22.
DOI: 10.1038/s41419-024-06894-1
Abstrakt: Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.
(© 2024. The Author(s).)
Databáze: MEDLINE
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