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Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy.

ABSTRACT: We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G2 DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP and WEE1 inhibitors could maintain efficacy while ameliorating toxicity. Strikingly, while sequential administration mirrored concurrent therapy in cancer cells that have high basal replication stress, low basal replication stress in normal cells protected them from DNA damage and toxicity, thus improving tolerability while preserving efficacy in ovarian cancer xenograft and patient-derived xenograft models.

SUBMITTER: Fang Y

PROVIDER: S-EPMC6642675 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy.

Fang Yong Y McGrail Daniel J DJ Sun Chaoyang C Labrie Marilyne M Chen Xiaohua X Zhang Dong D Ju Zhenlin Z Vellano Christopher P CP Lu Yiling Y Li Yongsheng Y Jeong Kang Jin KJ Ding Zhiyong Z Liang Jiyong J Wang Steven W SW Dai Hui H Lee Sanghoon S Sahni Nidhi N Mercado-Uribe Imelda I Kim Tae-Beom TB Chen Ken K Lin Shiaw-Yih SY Peng Guang G Westin Shannon N SN Liu Jinsong J O'Connor Mark J MJ Yap Timothy A TA Mills Gordon B GB

Cancer cell 20190601 6

We demonstrate that concurrent administration of poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors is effective in inhibiting tumor growth but poorly tolerated. Concurrent treatment with PARP and WEE1 inhibitors induces replication stress, DNA damage, and abrogates the G<sub>2</sub> DNA damage checkpoint in both normal and malignant cells. Following cessation of monotherapy with PARP or WEE1 inhibitors, effects of these inhibitors persist suggesting that sequential administration of PARP an ...[more]

PMID: 31185210

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Project description:The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination repair (HRR) is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.

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Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy.

Publications

Sequential Therapy with PARP and WEE1 Inhibitors Minimizes Toxicity while Maintaining Efficacy.

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