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control vs PARPi PEO4 at 1uM). (C)To investigate thein vivoimpact of prolonged PARPi, tumor [from a patient with a BRCA2MUT(8945delAA); WO-2-1] was transplanted to the fallopian tube/ovary of 10 NSG mice. colony formation and suppressed but did not eliminate tumor growth at the maximum-tolerated dose in a BRCAMUTPDX. PARPi treatment increased pATR and pCHK1 indicating activation from 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 to single agent remedies in BRCAMUTcells. Notably, PARPi led to G2 phase build up, and the addition of ATRi or CHK1i released cells from G2 causing premature mitotic access with increased chromosomal aberrations and apoptosis. Moreover, the combinations of PARPi with ATRi or CHK1i were synergistic in causing tumor suppression in a BRCAMUTPDX with the PARPi-ATRi combination inducing tumor regression and in most cases, complete remission. == Findings == PARPi causes increased reliance on ATR/CHK1 intended for genome stability and combination PARPi with ATR/CHK1i is more effective than PARPi alone in reducing tumor burden in BRCAMUTmodels. Keywords: ATR/CHK1, PARP inhibition, ovarian cancer == INTRODUCTION == Ovarian cancer survival offers improved minimally over the last decade(1) despite the unprecedented progress in understanding the genetics of ovarian cancer(2). There is a critical need to develop better therapeutic strategies that exploit the biology and genetics of high grade serous ovarian cancer (HGSOC). Approximately 50% of HGSOCs have defects in genes involved in homologous recombination (HR) repair(2, 3)BRCA 1and2(Breast Cancer Susceptibility Gene 1 and 2) mutant HGSOCs possess a deficiency in the repair of double strand DNA breaks (DSB) by HR(4). Poly (ADP-ribose) polymerase inhibitors (PARPi) impair the repair of single-stranded DNA breaks leading to DNA DSB which cannot be repaired efficiently in BRCA1/2-mutant (BRCAMUT) cancers capitalizing on synthetic lethality(5). PARPi, such as olaparib, have demonstrated a 31% overall response rate leading to its FDA approval intended for recurrent germline BRCAmutHGSOCs(6). Rare complete responses (3%) are seen with PARPi monotherapy(6-8). Our goal was to optimize PARPi therapy inBRCAMUTHGSOC by evaluating scientifically rational combinations. An additional approach to modulate DNA repair activity and improve the therapeutic index of PARPi in HR-deficient HGSOCs is to interfere with cell cycle checkpoint signaling. ATR (Ataxia Telengiectasia and Rad3-related) as well as downstream kinase CHK1 (Checkpoint Kinase 1), are activated by DNA replication stress and DNA damage thereby arresting cell cycle progression allowing time for appropriate damage repair and completion of replication(9, 10). ATR/CHK1 blockade prevents DNA-damage-induced cell cycle arrest, resulting in inappropriate entry into mitosis, chromosome aberrations, unequal partitioning from the genome, and ultimately apoptosis(9). In addition , because the ATR-CHK1 pathway stabilizes replication forks and prevents collapse into DNA double strand breaks (DSBs), inhibition of ATR/CHK1 are expected to Mirabegron increase reliance on HR to reform the replicatoin fork structure and complete replication. Indeed, ATR inhibition is synthetic lethal with several cancer-associated changes, including oncogenic stress (oncogenic RAS mutations, MYC and CCNE1 overexpression), deficiencies in DNA repair (TP53, BRCA1/2, PALB2, and ATM loss), and other defects(9, 11-15). CHK1 inhibition similarly, is synthetically lethal with p53 or BRCA 1/ 2 loss(16, 17). Almost all HGSOCs harbor a mutation in TP53(2) and thus have lost G1 checkpoint control, significantly increasing reliance on S and G2 checkpoints for survival(11, 18). Focusing on S and G2 checkpoints by inactivation of the ATR/CHK1 pathway will certainly inhibit the DNA damage induced G2 checkpoint arrest, leading to mitotic catastrophe and tumor cell death in contrast to normal cells, which maintain an intact G1-phase checkpoint(19). A variety of metabolic perturbations in cancers cause a reliance on ATR/CHK1 to facilitate DNA synthesis and prevent the formation of DNA double-stranded breaks (DSBs) at replication forks(20). These breaks can increase to toxic levels in cancer cells when ATR or CHK1 is inhibited(9, 11-14, 20-22). Thus, ATR or its downstream effector, CHK1, is a sensible target intended for treating HGSOCs, all of which NFKB1 possess loss of functional TP53 and approximately 50% have defects in HR(2). Drugs focusing on ATR (AZD6738, VX-970) and CHK1 (MK8776, SCH 900776, LY2606368, CCT245737) are in early phase I/II Mirabegron clinical trial development (clinicaltrials. gov). While PARPi is active because monotherapy, it rarely leads to complete tumor responses(6-8, 23), emphasizing the need for alternative strategies capitalizing on synthetic lethality. We have developed a BRCAMUTHGSOC orthotopic PDX platform with over 15 versions that is molecularly annotated to strategize synthetic lethal methods in BRCAMUTHGSOC(24). Mirabegron Because we observed that PARPi caused ATR-CHK1 pathway activation, we reasoned that PARPi treatment alone may increase dependence on the ATR/CHK1 pathway intended for.
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