Poly(adenosine diphosphate ribose) polymerase inhibitors induce autophagy‐mediated drug resistance in ovarian cancer cells, xenografts, and patient‐derived xenograft models

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 inhibi...

Full description

Saved in:
Bibliographic Details
Published in:Cancer 2020-02, Vol.126 (4), p.894-907
Main Authors: Santiago‐O’Farrill, Janice M., Weroha, S. John, Hou, Xiaonan, Oberg, Ann L., Heinzen, Ethan P., Maurer, Matthew J., Pang, Lan, Rask, Philip, Amaravadi, Ravi K., Becker, Sarah E., Romero, Ignacio, Rubio, Ma Jesús, Matias‐Guiu, Xavier, Santacana, Maria, Llombart‐Cussac, Antonio, Poveda, Andrés, Lu, Zhen, Bast, Robert C.
Format: Article
Language:English
Subjects:
Adenosine
Adenosine diphosphate
AKT protein
Animals
Antineoplastic Agents - pharmacology
Apoptosis
Apoptosis - drug effects
Autophagy
Autophagy - drug effects
Breast cancer
Cancer
Cell Line, Tumor
Chloroquine
Chloroquine - pharmacology
Drug resistance
Drug Resistance, Neoplasm - drug effects
Drug Synergism
Electron microscopy
Female
Fluorescence
Humans
Hydroxychloroquine
Indazoles - pharmacology
Inhibitors
Lipids
Mice, Nude
Mice, SCID
Oncology
Ovarian cancer
Ovarian Neoplasms - drug therapy
Ovarian Neoplasms - metabolism
Ovarian Neoplasms - pathology
Phagocytosis
Phagosomes
Phosphorylation
Phthalazines - pharmacology
Piperazines - pharmacology
Piperidines - pharmacology
poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Poly(ADP-ribose) Polymerases - metabolism
PTEN protein
Reactive oxygen species
resistance
Ribose
Sensitivity enhancement
siRNA
TOR protein
Xenograft Model Antitumor Assays - methods
Xenografts
Xenotransplantation
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. The data presented in this article show that poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors induce autophagy in 6 BRCA wild‐type ovarian cancer cells, which provides an adaptive mechanism of drug resistance. A combination of PARP inhibitors and autophagy inhibitors can overcome resistance and improve survival in different experimental models of ovarian cancer. These findings provide evidence of unique combinations of therapy for improving drug therapeutic efficacy, decreasing resistance, and extending the use of PARP inhibitors in the clinic.
ISSN:0008-543X
1097-0142
DOI:10.1002/cncr.32600