Abstract 4485: JPI-547, a novel dual inhibitor of PARP 1/2 and tankyrase 1/2 overcomes olaparib resistance in BRCA 1/2 mutant ovary and breast cancer preclinical model

Abstract

Abstract PARP inhibitors have prolonged the survival of various cancer patients with homologous recombination (HR) deficiencies. However, most patients eternally acquire resistance. Many attempts have been made, but there are no clear strategies to overcome resistance. We evaluated the efficacy and mechanism of JPI-547, a novel dual inhibitor of PARP1/2 and tankyrase1/2, in olaparib resistant breast and ovary preclinical cancer models. We established olaparib resistance models using mammalian cancer cell lines and patient-derived tumor xenografts (PDTXs). Two olaparib-resistant cells cell lines (BT474-OR/SNU251-OR) were established by exposing parent BRCA1/2 mutation carrying BT474 and SNU251 (breast and ovary cancer) to gradually increasing the concentration of olaparib for 8 months. An olaparib-resistant PDTX model [WJO-003(O2)], the parent BRCA1 mutation carrying ovary cancer PDTX was engrafted and treated with olaparib in 75mg/kg twice daily for 1 month and then 100mg/kg twice daily for 3 months. Using established olaparib resistance models, the anti-tumor efficacy of JPI-547 was compared with olaparib, niraparib, and talazoparib. IC50 of BT474-OR and SNU251-OR cell lines showed 5.5 and 6.7 fold increase compared to those of parent cell lines, respectively. While JPI-547 treatment in BT474-OR and SNU251-OR showed similar IC50 to the matching parent cells. In the PARPi-sensitive PDTX model, CPDX-013, JPI-547 inhibited tumor growth the greatest among other PARP inhibitors. Remarkably, 4 of 7 mice showed complete regression of the tumors. In the olaparib-resistant PDTX model, WJO-003(O2), JPI-547 inhibited tumor growth the most effectively compared to other PARP inhibitors (at day 60, the mean tumor volume: 2539, 1319, 871, 601, and 29 mm3 in control, niraparib, olaparib, talazoparib, and JPI-547, respectively; p<0.01). Since JPI-547 treated groups suppressed the tumor growth the most effectively both in olaparib-sensitive and resistant PDTX, to test whether JPI-547 is effective in prior PARPi-exposed tumor, we switched a PARPi to JPI-547 when most of PARPi treated tumors slowly retrieved the tumor growth. This subsequent treatment of JPI-547 completely suppressed the growth of tumor compared to a single other PARPi treated groups in both olaparib-sensitive and resistant models. The data suggest that JPI-547 efficiently inhibits growth of the tumor previously exposed to other PAPRi. JPI-547 treated tumors showed a decrease of RAD51 in comparison to other PARPi treated groups, which is likely mediated by inhibition of tankyrase 1/2 by JPI-547 and suppression of TNK1/2-MERIT40 complex. Then this suppression resulted in blockade of HR repair.JPI-547 showed promising efficacy in an olaparib-resistant preclinical model. JPI-547 merits further clinical development in the PARP inhibitor-resistant ovary and breast cancer. Citation Format: Min Sil Kang, Nar Katuwal, Mithun Ghosh, Young kyu Jeong, Sa deok Hong, Sung Min Park, John Kim, Hyunju Cha, Banyoon Cheon, Seul-Gi Kim, Yong Wha Moon. JPI-547, a novel dual inhibitor of PARP 1/2 and tankyrase 1/2 overcomes olaparib resistance in BRCA 1/2 mutant ovary and breast cancer preclinical model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4485.