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

PARP inhibition (PARPi) has modest clinical activity in recurrent -mutant () 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. 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 HGSOC cells. Tumor growth was evaluated using a patient-derived xenograft (PDX) model. PARPi monotherapy resulted in a decrease in cell survival, colony formation and suppressed but did not eliminate tumor growth at the maximum tolerated dose (MTD) in a 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 cells. Notably, PARPi led to G phase accumulation, and the addition of ATRi or CHK1i released cells from G 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 PDX with the PARPi-ATRi combination inducing tumor regression and in most cases, complete remission. 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 models. .