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.

• Authors: 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
• Journal: Cancer cell (Cancer Cell) Vol. 35 Issue 6 Pg. 851-867.e7 (06 10 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 31185210 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published by Elsevier Inc.

Chemical References

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

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology, toxicity)
• Cell Cycle Proteins (antagonists & inhibitors, genetics, 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, enzymology, genetics, pathology)
• Poly(ADP-ribose) Polymerase Inhibitors (administration & dosage, toxicity)
• Protein Kinase Inhibitors (administration & dosage, toxicity)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction
• Time Factors
• Tumor Burden (drug effects)