Characterization of a RAD51C -silenced high-grade serous ovarian cancer model during development of PARP inhibitor resistance.

Autor:	Hurley RM; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., McGehee CD; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., Nesic K; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia., Correia C; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., Weiskittel TM; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., Kelly RL; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., Venkatachalam A; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., Hou X; Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 USA., Pathoulas NM; Division of Oncology Research, Mayo Clinic, Rochester, MN 55905 USA., Meng XW; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., Kondrashova O; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia., Radke MR; Department of Obstetrics & Gynecology, University of Washington, Seattle, WA 98195, USA., Schneider PA; Division of Oncology Research, Mayo Clinic, Rochester, MN 55905 USA., Flatten KS; Division of Oncology Research, Mayo Clinic, Rochester, MN 55905 USA., Peterson KL; Division of Oncology Research, Mayo Clinic, Rochester, MN 55905 USA., Becker MA; Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 USA., Wong EM; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria 3800, Australia., Southey MS; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria 3800, Australia., Dobrovic A; University of Melbourne Department of Surgery, Austin Hospital, Heidelberg, Victoria 3084, Australia., Lin KK; Clovis Oncology, San Francisco, CA 94158, USA., Harding TC; Clovis Oncology, San Francisco, CA 94158, USA., McNeish I; Division of Cancer, Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, London, W12 0NN United Kingdom., Ross CA; Division of Information Technology, Mayo Clinic, Rochester, MN 55905, USA., Wagner JM; Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 USA., Wakefield MJ; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia., Scott CL; The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia., Haluska P; Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 USA., Wahner Hendrickson AE; Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 USA., Karnitz LM; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., Swisher EM; Department of Obstetrics & Gynecology, University of Washington, Seattle, WA 98195, USA., Li H; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA., Weroha SJ; Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905 USA., Kaufmann SH; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905 USA.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2021 Jul 09; Vol. 3 (3), pp. zcab028. Date of Electronic Publication: 2021 Jul 09 (Print Publication: 2021).
DOI:	10.1093/narcan/zcab028
Abstrakt:	Acquired PARP inhibitor (PARPi) resistance in BRCA1 - or BRCA2 -mutant ovarian cancer often results from secondary mutations that restore expression of functional protein. RAD51C is a less commonly studied ovarian cancer susceptibility gene whose promoter is sometimes methylated, leading to homologous recombination (HR) deficiency and PARPi sensitivity. For this study, the PARPi-sensitive patient-derived ovarian cancer xenograft PH039, which lacks HR gene mutations but harbors RAD51C promoter methylation, was selected for PARPi resistance by cyclical niraparib treatment in vivo . PH039 acquired PARPi resistance by the third treatment cycle and grew through subsequent treatment with either niraparib or rucaparib. Transcriptional profiling throughout the course of resistance development showed widespread pathway level changes along with a marked increase in RAD51C mRNA, which reflected loss of RAD51C promoter methylation. Analysis of ovarian cancer samples from the ARIEL2 Part 1 clinical trial of rucaparib monotherapy likewise indicated an association between loss of RAD51C methylation prior to on-study biopsy and limited response. Interestingly, the PARPi resistant PH039 model remained platinum sensitive. Collectively, these results not only indicate that PARPi treatment pressure can reverse RAD51C methylation and restore RAD51C expression, but also provide a model for studying the clinical observation that PARPi and platinum sensitivity are sometimes dissociated. (© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
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