PTEN deficiency confers sensitivity to ATR inhibitor-based treatment in high-grade serous ovarian cancer

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Abstract

ATR inhibition is under evaluation for 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 response to ATR inhibition, as monotherapy and in combination with PARP inhibition or gemcitabine. In response to ATR inhibition and compared to PTEN-proficient cells, PTEN-deficient cells are prone to (1) uncoupling of DNA polymerase and helicase activities, leading to excessive single-stranded DNA and replication stress; (2) cytoplasmic sequestration of CHK1, compromising cell cycle checkpoint control with reduced compensatory effects by ATM and DNA-PK, leading to mitotic catastrophe; and (3) reduced RAD51 recruitment, exacerbating replication fork instability, also leading to lethality. Retrospective analyses demonstrate that patients with HGSOC expressing low PTEN levels experience greater clinical benefit on ATR inhibitor-based trials than those with high 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 Andre 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 L. Gaillard, Robert L. Giuntoli II, Lainie P. Martin, Janos L. Tanyi, Nawar Latif, Ian S. Heller, Fiona Simpkins, Kalindi Parmar, Alan D. D'Andrea, Geoffrey I. Shapiro