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

Yong Fang; Daniel J McGrail; Chaoyang Sun; Marilyne Labrie; Xiaohua Chen; Dong Zhang; Zhenlin Ju; Christopher P Vellano; Yiling Lu; Yongsheng Li; Kang Jin Jeong; Zhiyong Ding; Jiyong Liang; Steven W Wang; Hui Dai; Sanghoon Lee; Nidhi Sahni; Imelda Mercado-Uribe; Tae-Beom Kim; Ken Chen; Shiaw-Yih Lin; Guang Peng; Shannon N Westin; Jinsong Liu; Mark J O'Connor; Timothy A Yap; Gordon B Mills

doi:10.1016/j.ccell.2019.05.001

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

Cancer Cell. 2019 Jun 10;35(6):851-867.e7. doi: 10.1016/j.ccell.2019.05.001.

Authors

Yong Fang¹, Daniel J McGrail², Chaoyang Sun³, Marilyne Labrie⁴, Xiaohua Chen², Dong Zhang⁴, Zhenlin Ju², Christopher P Vellano², Yiling Lu², Yongsheng Li², Kang Jin Jeong⁴, Zhiyong Ding², Jiyong Liang², Steven W Wang², Hui Dai², Sanghoon Lee², Nidhi Sahni⁵, Imelda Mercado-Uribe⁶, Tae-Beom Kim⁷, Ken Chen⁷, Shiaw-Yih Lin², Guang Peng⁸, Shannon N Westin⁹, Jinsong Liu⁶, Mark J O'Connor¹⁰, Timothy A Yap¹¹, Gordon B Mills⁴

Affiliations

¹ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cell, Development and Cancer Biology, Oregon Health and Sciences University, Portland, OR 97201, USA; Knight Cancer Institute, Portland, OR 97201, USA; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
² Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: [email protected].
⁴ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cell, Development and Cancer Biology, Oregon Health and Sciences University, Portland, OR 97201, USA; Knight Cancer Institute, Portland, OR 97201, USA.
⁵ Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.
⁶ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁷ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Oncology, Innovative Medicines and Early Clinical Development, AstraZeneca, Cambridge CB4 0WG, UK.
¹¹ Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

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.

Keywords: PARP inhibitor; WEE1 inhibitor; replication stress; sequential therapy.

Published by Elsevier Inc.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / toxicity
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
DNA Damage
Drug Administration Schedule
Female
G2 Phase Cell Cycle Checkpoints / drug effects
Heterografts
Humans
Mice, Inbred C57BL
Mice, Nude
Mice, SCID
Mitosis / drug effects
Neoplasms / drug therapy*
Neoplasms / enzymology
Neoplasms / genetics
Neoplasms / pathology
Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage*
Poly(ADP-ribose) Polymerase Inhibitors / toxicity
Protein Kinase Inhibitors / administration & dosage*
Protein Kinase Inhibitors / toxicity
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Signal Transduction
Time Factors
Tumor Burden / drug effects

Substances

Cell Cycle Proteins
Poly(ADP-ribose) Polymerase Inhibitors
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
WEE1 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding