An effective epigenetic-PARP inhibitor combination therapy for breast and ovarian cancers independent of BRCA mutations

Nicholas Pulliam, Fang Fang, Ali R. Ozes, Jessica Tang, Adeoluwa Adewuyi, Harold Keer, John Lyons, Stephen B. Baylin, Daniela Matei, Harikrishna Nakshatri, Feyruz V. Rassool, Kathy Miller, Kenneth Nephew

Research output: Contribution to journalArticle

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Abstract

Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status. Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed. Results: Combination of guadecitabine and talazoparib syner-gized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP "trapping" by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models. Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type– or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.

Original languageEnglish (US)
Pages (from-to)3163-3175
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number13
DOIs
StatePublished - Jul 1 2018

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Epigenomics
Ovarian Neoplasms
Breast Neoplasms
Mutation
Methyltransferases
DNA
Therapeutics
Neoplasms
Poly(ADP-ribose) Polymerase Inhibitors
Triple Negative Breast Neoplasms
Drug Combinations
talazoparib
Heterografts
DNA Repair
SGI-110
Cell Survival
Research Design
Gene Expression
Cell Line
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

An effective epigenetic-PARP inhibitor combination therapy for breast and ovarian cancers independent of BRCA mutations. / Pulliam, Nicholas; Fang, Fang; Ozes, Ali R.; Tang, Jessica; Adewuyi, Adeoluwa; Keer, Harold; Lyons, John; Baylin, Stephen B.; Matei, Daniela; Nakshatri, Harikrishna; Rassool, Feyruz V.; Miller, Kathy; Nephew, Kenneth.

In: Clinical Cancer Research, Vol. 24, No. 13, 01.07.2018, p. 3163-3175.

Research output: Contribution to journalArticle

Pulliam, Nicholas ; Fang, Fang ; Ozes, Ali R. ; Tang, Jessica ; Adewuyi, Adeoluwa ; Keer, Harold ; Lyons, John ; Baylin, Stephen B. ; Matei, Daniela ; Nakshatri, Harikrishna ; Rassool, Feyruz V. ; Miller, Kathy ; Nephew, Kenneth. / An effective epigenetic-PARP inhibitor combination therapy for breast and ovarian cancers independent of BRCA mutations. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 13. pp. 3163-3175.
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abstract = "Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status. Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed. Results: Combination of guadecitabine and talazoparib syner-gized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP {"}trapping{"} by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models. Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type– or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.",
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T1 - An effective epigenetic-PARP inhibitor combination therapy for breast and ovarian cancers independent of BRCA mutations

AU - Pulliam, Nicholas

AU - Fang, Fang

AU - Ozes, Ali R.

AU - Tang, Jessica

AU - Adewuyi, Adeoluwa

AU - Keer, Harold

AU - Lyons, John

AU - Baylin, Stephen B.

AU - Matei, Daniela

AU - Nakshatri, Harikrishna

AU - Rassool, Feyruz V.

AU - Miller, Kathy

AU - Nephew, Kenneth

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status. Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed. Results: Combination of guadecitabine and talazoparib syner-gized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP "trapping" by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models. Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type– or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.

AB - Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status. Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed. Results: Combination of guadecitabine and talazoparib syner-gized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP "trapping" by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models. Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type– or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers.

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