Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models

被引：251

作者：

Kim, Hyoung ^{[1
]}

Xu, Haineng ^{[1
]}

George, Erin ^{[1
]}

Hallberg, Dorothy ^{[2
]}

Kumar, Sushil ^{[1
]}

Jagannathan, Veena ^{[3
]}

Medvedev, Sergey ^{[1
]}

Kinose, Yasuto ^{[1
]}

Devins, Kyle ^{[4
]}

Verma, Priyanka ^{[3
]}

Ly, Kevin ^{[1
]}

Wang, Yifan ^{[5
]}

Greenberg, Roger A. ^{[3
]}

Schwartz, Lauren ^{[4
]}

Johnson, Neil ^{[5
]}

Scharpf, Robert B. ^{[2
]}

Mills, Gordon B. ^{[6
]}

Zhang, Rugang ^{[7
]}

Velculescu, Victor E. ^{[2
]}

Brown, Eric J. ^{[3
]}

Simpkins, Fiona ^{[1
]}

机构：

[1] Univ Penn, Penn Ovarian Canc Res Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Philadelphia, PA 19104 USA

[2] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Sch Med, Baltimore, MD 21287 USA

[3] Univ Penn, Perelman Sch Med, Dept Canc Biol, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[5] Fox Chase Canc Ctr, Mol Therapeut Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[6] Oregon Hlth & Sci Univ, Dept Cell Dev & Canc Biol, Sch Med, Portland, OR 97239 USA

[7] Wistar Inst Anat & Biol, Gene Express & Regulat Program, 3601 Spruce St, Philadelphia, PA 19104 USA

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

HOMOLOGOUS RECOMBINATION; GENOMIC INSTABILITY; SYNTHETIC LETHALITY; REPLICATION FORKS; THERAPY; PROTEIN; PROTECTION; MUTATIONS; KINASE; AMPLIFICATION;

D O I：

10.1038/s41467-020-17127-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ovarian cancer (OVCA) inevitably acquires resistance to platinum chemotherapy and PARP inhibitors (PARPi). We show that acquisition of PARPi-resistance is accompanied by increased ATR-CHK1 activity and sensitivity to ATR inhibition (ATRi). However, PARPi-resistant cells are remarkably more sensitive to ATRi when combined with PARPi (PARPi-ATRi). Sensitivity to PARPi-ATRi in diverse PARPi and platinum-resistant models, including BRCA1/2 reversion and CCNE1-amplified models, correlate with synergistic increases in replication fork stalling, double-strand breaks, and apoptosis. Surprisingly, BRCA reversion mutations and an ability to form RAD51 foci are frequently not observed in models of acquired PARPi-resistance, suggesting the existence of alternative resistance mechanisms. However, regardless of the mechanisms of resistance, complete and durable therapeutic responses to PARPi-ATRi that significantly increase survival are observed in clinically relevant platinum and acquired PARPi-resistant patient-derived xenografts (PDXs) models. These findings indicate that PARPi-ATRi is a highly promising strategy for OVCAs that acquire resistance to PARPi and platinum. Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models.

引用

页数：16

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