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

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 G₂ phase accumulation, and the addition of ATRi or CHK1i released cells from G₂ 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.

http://ift.tt/2sqZ2mk