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Purpose: PARP inhibition (PARPi) has modest clinical activity in recurrent BRCA -mutant ( BRCA  MUT ) high-grade serous ovarian cancers (HGSOC). We hypothesized that PARPi increases dependence on ATR/CHK1 such that combination PARPi with ATR/CHK1 blockade results in increased cell death and tumor regression. Experimental Design: Effects of PARPi (olaparib), CHK1 inhibition (CHK1i;MK8776), or ATR inhibition (ATRi;AZD6738) alone or in combination on survival, colony formation, cell cycle, genome instability, and apoptosis were evaluated in BRCA1/2  MUT HGSOC cells. Tumor growth in vivo was evaluated using a BRCA2  MUT patient-derived xenograft (PDX) model. Results: PARPi monotherapy resulted in a decrease in BRCA  MUT cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a BRCA2  MUT PDX. PARPi treatment increased pATR and pCHK1, indicating activation of the ATR-CHK1 fork protection pathway is relied upon for genome stability under PARPi. Indeed, combination of ATRi or CHK1i with PARPi synergistically decreased survival and colony formation compared with single-agent treatments in BRCA  MUT cells. Notably, PARPi led to G 2 phase accumulation, and the addition of ATRi or CHK1i released cells from G 2 causing premature mitotic entry with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCA2  MUT PDX with the PARPi-ATRi combination inducing tumor regression and in most cases, complete remission. Conclusions: PARPi causes increased reliance on ATR/CHK1 for genome stability, and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCA  MUT models. Clin Cancer Res; 23(12); 3097-108. ©2016 AACR .

Targeting the ATR/CHK1 Axis with PARP Inhibition Results in Tumor Regression in BRCA-Mutant Ovarian Cancer Models