Abstract
Ataxia telangiectasia and Rad3-related (ATR) inhibition is under evaluation for the treatment of high-grade serous ovarian cancer (HGSOC) to reverse acquired resistance to poly (ADP-ribose) polymerase (PARP) inhibition and to exacerbate chemotherapy-induced replicative stress. Here, we define PTEN deficiency as a predictive biomarker for the response to ATR inhibition, as monotherapy and in combination with PARP inhibition or gemcitabine. In response to ATR inhibition and compared with PTEN-proficient cells, PTEN-deficient cells are prone to (a) uncoupling of DNA polymerase and helicase activities, leading to excessive ssDNA and replication stress; (b) cytoplasmic sequestration of checkpoint kinase 1 (CHK1), compromising cell-cycle checkpoint control with reduced compensatory effects by ataxia-telangiectasia mutated (ATM) and DNA–dependent proteinase K (DNA-PK), leading to mitotic catastrophe; and (c) reduced DNA repair protein RAD51 homolog 1 (RAD51) recruitment, exacerbating replication fork instability, also leading to lethality. Retrospective analyses revealed that patients with HGSOC who expressed low PTEN levels experienced greater clinical benefit on ATR inhibitor–based trials than did those with high PTEN levels. These results justify prospective trials evaluating ATR inhibition as a therapeutic strategy for PTEN-deficient tumors.
Authors
Jie Hao, Bose Kochupurakkal, Timothy B. Branigan, Ozge Sezin Somuncu, Renyan Liu, Heta Jadhav, Alexandre André B. A. da Costa, Yuqing Jiao, Jenny Z. Yu, David B. Martignetti, Golbahar Sadatrezaei, Sirisha Mukkavalli, Prafulla C. Gokhale, Su-Chun Cheng, Steven J. Skates, Dimitrios Nasioudis, Panagiotis A. Konstantinopoulos, Joyce F. Liu, Stephanie Gaillard, Robert L. Giuntoli II, Lainie Martin, Janos Tanyi, Nawar Latif, Ian Heller, Fiona Simpkins, Kalindi Parmar, Alan D. D’Andrea, Geoffrey I. Shapiro
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ISSN: 0021-9738 (print), 1558-8238 (online)