PTEN deficiency confers sensitivity to ATR inhibitor–based treatment in high-grade serous ovarian cancer
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
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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Research Article Cell biology Clinical Research Oncology

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

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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Figure 4

PTEN loss impairs RAD51-mediated fork protection following ATR inhibition.

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PTEN loss impairs RAD51-mediated fork protection following ATR inhibitio...
(A) DNA fiber assay assessing replication fork stability in PTEN WT and PTEN-KO cells. IdU and CldU track lengths were measured using ImageJ, and the IdU/CldU ratio was calculated to indicate fork stability. (B) DNA fiber assay in 3 organoid models treated with niraparib, tuvusertib, or their combination. ATR inhibition induced fork instability only in PTEN-deficient models. (C) Western blot analysis of chromatin-bound fractions from PTEN WT and PTEN-KO cells following ATR inhibitor treatment, showing reduced RAD51 accumulation in PTEN-deficient cells. (D) Immunofluorescence staining for RAD51 foci in OVCAR8 PTEN WT and PTEN-KO cells treated with DMSO, niraparib, tuvusertib, or their combination. Scale bars: 10 μm. (E) Quantification of RAD51 foci per cell. Each dot represents an individual DNA fiber (A and B) or cell (E) from 3 independent experiments. Symbols represent the mean value of each biological replicate. Data are presented as the mean ± SD (n = 3 independent experiments per group). At least 100 DNA fibers (A and B) or 200 cells (E) were analyzed per experiment. Statistical analyses were performed using biological replicate means and assessed by 1-way ANOVA with Tukey’s multiple-comparison test (*P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001).