The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance

Melissa M. Pham; Emily Hinchcliff; Monica Avila; Shannon N. Westin

doi:10.1097/PPO.0000000000000562

The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance

Melissa M. Pham, Emily Hinchcliff, Monica Avila, Shannon N. Westin^*

^*Corresponding author for this work

Obstetrics and Gynecology

Research output: Contribution to journal › Review article › peer-review

6 Scopus citations

Abstract

The use of poly(ADP-ribose) polymerase inhibitor (PARPi) exploits synthetic lethality in solid tumors with homologous recombination repair (HRR) defects. Significant clinical benefit has been established in breast and ovarian cancers harboring BRCA1/2 mutations, as well as tumors harboring characteristics of "BRCAness."However, the durability of treatment responses is limited, and emerging data have demonstrated the clinical challenge of PARPi resistance. With the expanding use of PARPi, the significance of PARP therapy in patients pretreated with PARPi remains in need of significant further investigation. Molecular mechanisms contributing to this phenomenon include restoration of HRR function, replication fork stabilization, BRCA1/2 reversion mutations, and epigenetic changes. Current studies are evaluating the utility of combination therapies of PARPi with cell cycle checkpoint inhibitors, antiangiogenic agents, phosphatidylinositol 3-kinase/AKT pathway inhibitors, MEK inhibitors, and epigenetic modifiers to overcome this resistance. In this review, we address the mechanisms of PARPi resistance supported by preclinical models, examine current clinical trials applying combination therapy to overcome PARPi resistance, and discuss future directions to enhance the clinical efficacy of PARPi.

Original language	English (US)
Pages (from-to)	491-500
Number of pages	10
Journal	Cancer Journal (United States)
Volume	27
Issue number	6
DOIs	https://doi.org/10.1097/PPO.0000000000000562
State	Published - Dec 27 2021

Funding

Conflicts of Interest and Source of Funding: S.N.W. has clinical research funding from ArQule, AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, Novartis, Roche/Genentech, and Tesaro. S.N.W. receives consulting fees from AstraZeneca, Clovis Oncology, MediVation, Merck, Ovation, Pfizer, Takeda, and Tesaro. This work was also supported in part by the MD Anderson Cancer Center Support Grant from the National Cancer Institute of the National Institutes of Health (NIH/NCI P30 CA016672), Ovarian SPORE NIH 1P50CA217685-01, the GOG Foundation, and the T32 training grant (NIH/NCI CA101642). For the remaining authors, none were declared.

Keywords

Homologous recombination
PARPi
PARPi combination therapy
PARPi resistance

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1097/PPO.0000000000000562

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title = "The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance",

abstract = "The use of poly(ADP-ribose) polymerase inhibitor (PARPi) exploits synthetic lethality in solid tumors with homologous recombination repair (HRR) defects. Significant clinical benefit has been established in breast and ovarian cancers harboring BRCA1/2 mutations, as well as tumors harboring characteristics of {"}BRCAness.{"}However, the durability of treatment responses is limited, and emerging data have demonstrated the clinical challenge of PARPi resistance. With the expanding use of PARPi, the significance of PARP therapy in patients pretreated with PARPi remains in need of significant further investigation. Molecular mechanisms contributing to this phenomenon include restoration of HRR function, replication fork stabilization, BRCA1/2 reversion mutations, and epigenetic changes. Current studies are evaluating the utility of combination therapies of PARPi with cell cycle checkpoint inhibitors, antiangiogenic agents, phosphatidylinositol 3-kinase/AKT pathway inhibitors, MEK inhibitors, and epigenetic modifiers to overcome this resistance. In this review, we address the mechanisms of PARPi resistance supported by preclinical models, examine current clinical trials applying combination therapy to overcome PARPi resistance, and discuss future directions to enhance the clinical efficacy of PARPi.",

keywords = "Homologous recombination, PARPi, PARPi combination therapy, PARPi resistance",

author = "Pham, {Melissa M.} and Emily Hinchcliff and Monica Avila and Westin, {Shannon N.}",

note = "Funding Information: Conflicts of Interest and Source of Funding: S.N.W. has clinical research funding from ArQule, AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, Novartis, Roche/Genentech, and Tesaro. S.N.W. receives consulting fees from AstraZeneca, Clovis Oncology, MediVation, Merck, Ovation, Pfizer, Takeda, and Tesaro. This work was also supported in part by the MD Anderson Cancer Center Support Grant from the National Cancer Institute of the National Institutes of Health (NIH/NCI P30 CA016672), Ovarian SPORE NIH 1P50CA217685-01, the GOG Foundation, and the T32 training grant (NIH/NCI CA101642). For the remaining authors, none were declared. Publisher Copyright: {\textcopyright} Wolters Kluwer Health, Inc. All rights reserved.",

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AU - Westin, Shannon N.

N1 - Funding Information: Conflicts of Interest and Source of Funding: S.N.W. has clinical research funding from ArQule, AstraZeneca, Bayer, Clovis Oncology, Cotinga Pharmaceuticals, Novartis, Roche/Genentech, and Tesaro. S.N.W. receives consulting fees from AstraZeneca, Clovis Oncology, MediVation, Merck, Ovation, Pfizer, Takeda, and Tesaro. This work was also supported in part by the MD Anderson Cancer Center Support Grant from the National Cancer Institute of the National Institutes of Health (NIH/NCI P30 CA016672), Ovarian SPORE NIH 1P50CA217685-01, the GOG Foundation, and the T32 training grant (NIH/NCI CA101642). For the remaining authors, none were declared. Publisher Copyright: © Wolters Kluwer Health, Inc. All rights reserved.

PY - 2021/12/27

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N2 - The use of poly(ADP-ribose) polymerase inhibitor (PARPi) exploits synthetic lethality in solid tumors with homologous recombination repair (HRR) defects. Significant clinical benefit has been established in breast and ovarian cancers harboring BRCA1/2 mutations, as well as tumors harboring characteristics of "BRCAness."However, the durability of treatment responses is limited, and emerging data have demonstrated the clinical challenge of PARPi resistance. With the expanding use of PARPi, the significance of PARP therapy in patients pretreated with PARPi remains in need of significant further investigation. Molecular mechanisms contributing to this phenomenon include restoration of HRR function, replication fork stabilization, BRCA1/2 reversion mutations, and epigenetic changes. Current studies are evaluating the utility of combination therapies of PARPi with cell cycle checkpoint inhibitors, antiangiogenic agents, phosphatidylinositol 3-kinase/AKT pathway inhibitors, MEK inhibitors, and epigenetic modifiers to overcome this resistance. In this review, we address the mechanisms of PARPi resistance supported by preclinical models, examine current clinical trials applying combination therapy to overcome PARPi resistance, and discuss future directions to enhance the clinical efficacy of PARPi.

AB - The use of poly(ADP-ribose) polymerase inhibitor (PARPi) exploits synthetic lethality in solid tumors with homologous recombination repair (HRR) defects. Significant clinical benefit has been established in breast and ovarian cancers harboring BRCA1/2 mutations, as well as tumors harboring characteristics of "BRCAness."However, the durability of treatment responses is limited, and emerging data have demonstrated the clinical challenge of PARPi resistance. With the expanding use of PARPi, the significance of PARP therapy in patients pretreated with PARPi remains in need of significant further investigation. Molecular mechanisms contributing to this phenomenon include restoration of HRR function, replication fork stabilization, BRCA1/2 reversion mutations, and epigenetic changes. Current studies are evaluating the utility of combination therapies of PARPi with cell cycle checkpoint inhibitors, antiangiogenic agents, phosphatidylinositol 3-kinase/AKT pathway inhibitors, MEK inhibitors, and epigenetic modifiers to overcome this resistance. In this review, we address the mechanisms of PARPi resistance supported by preclinical models, examine current clinical trials applying combination therapy to overcome PARPi resistance, and discuss future directions to enhance the clinical efficacy of PARPi.

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JO - Cancer Journal (United States)

JF - Cancer Journal (United States)

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ER -

The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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