@article{9795275e27144da48f72b360293a4a8d,
title = "Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy-mediated drug resistance in ovarian cancer cells, xenografts, and patient-derived xenograft models",
abstract = "Background: Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors exhibit promising activity against ovarian cancers, but their efficacy can be limited by acquired drug resistance. This study explores the role of autophagy in regulating the sensitivity of ovarian cancer cells to PARP inhibitors. Methods: Induction of autophagy was detected by punctate LC3 fluorescence staining, LC3I to LC3II conversion on Western blot analysis, and electron microscopy. Enhanced growth inhibition and apoptosis were observed when PARP inhibitors were used with hydroxychloroquine, chloroquine (CQ), or LYS05 to block the hydrolysis of proteins and lipids in autophagosomes or with small interfering RNA against ATG5 or ATG7 to prevent the formation of autophagosomes. The preclinical efficacy of the combination of CQ and olaparib was evaluated with a patient-derived xenograft (PDX) and the OVCAR8 human ovarian cancer cell line. Results: Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) induced autophagy in a panel of ovarian cancer cells. Inhibition of autophagy with CQ enhanced the sensitivity of ovarian cancer cells to PARP inhibitors. In vivo, olaparib and CQ produced additive growth inhibition in OVCAR8 xenografts and a PDX. Olaparib inhibited PARP activity, and this led to increased reactive oxygen species (ROS) and an accumulation of γ-H2AX. Inhibition of autophagy also increased ROS and γ-H2AX and enhanced the effect of olaparib on both entities. Treatment with olaparib increased phosphorylation of ATM and PTEN while decreasing the phosphorylation of AKT and mTOR and inducing autophagy. Conclusions: PARP inhibitor–induced autophagy provides an adaptive mechanism of resistance to PARP inhibitors in cancer cells with wild-type BRCA, and a combination of PARP inhibitors with CQ or other autophagy inhibitors could improve outcomes for patients with ovarian cancer.",
keywords = "autophagy, ovarian cancer, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, resistance",
author = "Santiago-O{\textquoteright}Farrill, {Janice M.} and Weroha, {S. John} and Xiaonan Hou and Oberg, {Ann L.} and Heinzen, {Ethan P.} and Maurer, {Matthew J.} and Lan Pang and Philip Rask and Amaravadi, {Ravi K.} and Becker, {Sarah E.} and Ignacio Romero and Rubio, {Ma Jes{\'u}s} and Xavier Matias-Guiu and Maria Santacana and Antonio Llombart-Cussac and Andr{\'e}s Poveda and Zhen Lu and Bast, {Robert C.}",
note = "Funding Information: This work was supported by the Cancer Prevention and Research Institute of Texas (RP110595‐P1), the National Cancer Institute (R01 CA 135354), the National Institutes of Health/National Cancer Institute (Diversity Supplement R01CA135354), the MD Anderson Specialized Program of Research Excellence in Ovarian Cancer (P50 CA 83639 and CA 217685 from the National Cancer Institute), the Mayo Clinic Specialized Program of Research Excellence in Ovarian Cancer (CA136393), the Shared Resources of the MD Anderson Cancer Center Support Grant (P30 CA16672 from the National Cancer Institute), the National Foundation for Cancer Research, and philanthropic support through generous donations from Stuart and Gaye‐Lynn Zarrow, the Mossy Foundation, and the Roberson Endowment. Sarah E. Becker was supported by the CPRIT Research Training Program (RP 170067). Funding Information: S. John Weroha receives royalties for a patent on ovarian cancer avatars. Matthew J. Maurer reports grants from Celgene and Nanostring and personal fees from Morphosys outside the submitted work. Ravi K. Amaravadi is the founder of Pinpoint Therapeutics and is the inventor on 3 patents related to LYS05; he also reports working as a scientific advisor for Immunaccel and Sprint Biosciences and receiving personal fees from Deciphera Pharmaceuticals and Array Pharmaceuticals outside the submitted work. Ignacio Romero reports grants and nonfinancial support from the Valencian Institute of Oncology during the conduct of the study; personal fees and nonfinancial support from AstraZeneca, Roche, Tesaro GSK, and PharmaMar; and personal fees from Clovis outside the submitted work. Xavier Matias‐Guiu and Maria Santacana report grants and nonfinancial support from the Lleida Biomedical Research Institute during the conduct of the study. Antonio Llombart‐Cussac reports personal fees from AstraZeneca, Novartis, Puma, and Amgen; grants, personal fees, and nonfinancial support from Pfizer and Roche/Genentech; grants and personal fees from Lilly and Tesaro GSK; stock from Medica Scientia Innovation Research; and grants and nonfinancial support from Eisai outside the submitted work. Andr{\'e}s Poveda reports personal financial interests in AstraZeneca, Clovis Oncology, Tesaro GSK, PharmaMar, Roche, Pfizer, Bayer, Janssen, and Novartis/Sandoz and nonfinancial interests in Deciphera (an independent data monitoring committee member) and Regeneron Pharmaceuticals (a steering committee member); he was the global clinical lead for the olaparib study OPINION (AstraZeneca); and he participated in the olaparib studies SOLO2 and SOLO1 (AstraZeneca) and the rucaparib studies ARIEL2 and ARIEL3 (Clovis). The other authors made no disclosures. Funding Information: This work was supported by the Cancer Prevention and Research Institute of Texas (RP110595‐P1), the National Cancer Institute (R01 CA 135354), the National Institutes of Health/National Cancer Institute (Diversity Supplement R01CA135354), the MD Anderson Specialized Program of Research Excellence in Ovarian Cancer (P50 CA 83639 and CA 217685 from the National Cancer Institute), the Mayo Clinic Specialized Program of Research Excellence in Ovarian Cancer (CA136393), the Shared Resources of the MD Anderson Cancer Center Support Grant (P30 CA16672 from the National Cancer Institute), the National Foundation for Cancer Research, and philanthropic support through generous donations from Stuart and Gaye‐Lynn Zarrow, the Mossy Foundation, and the Roberson Endowment. Publisher Copyright: {\textcopyright} 2019 American Cancer Society",
year = "2020",
month = feb,
day = "15",
doi = "10.1002/cncr.32600",
language = "English (US)",
volume = "126",
pages = "894--907",
journal = "Cancer",
issn = "0008-543X",
publisher = "John Wiley and Sons Inc.",
number = "4",
}