In vivo anti-tumor activity of the PARP inhibitor niraparib in homologous recombination deficient and proficient ovarian carcinoma

Abstract

Objective Poly(ADP-ribose) polymerase (PARP) inhibitors have yielded encouraging responses in high-grade serous ovarian carcinomas (HGSOCs), but the optimal treatment setting remains unknown. We assessed the effect of niraparib on HGSOC patient-derived xenograft (PDX) models as well as the relationship between certain markers of homologous recombination (HR) status, including BRCA1/2 mutations and formation of RAD51 foci after DNA damage, and response of these PDXs to niraparib in vivo. Methods Massively parallel sequencing was performed on HGSOCs to identify mutations contributing to HR deficiency. HR pathway integrity was assessed using fluorescence microscopy-based RAD51 focus formation assays. Effects of niraparib (MK-4827) on treatment-naïve PDX tumor growth as monotherapy, in combination with carboplatin/paclitaxel, and as maintenance therapy were assessed by transabdominal ultrasound. Niraparib responses were correlated with changes in levels of poly(ADP-ribose), PARP1, and repair proteins by western blotting. Results Five PDX models were evaluated in vivo. Tumor regressions were induced by single-agent niraparib in one of two PDX models with deleterious BRCA2 mutations and in a PDX with RAD51C promoter methylation. Diminished formation of RAD51 foci failed to predict response, but Artemis loss was associated with resistance. Niraparib generally failed to enhance responses to carboplatin/paclitaxel chemotherapy, but maintenance niraparib therapy delayed progression in a BRCA2-deficient PDX. Conclusions Mutations in HR genes are neither necessary nor sufficient to predict response to niraparib. Assessment of repair status through multiple complementary assays is needed to guide PARP inhibitor therapy, design future clinical trials and identify ovarian cancer patients most likely to benefit from PARP inhibition.

Acquired resistance of phosphatase and tensin homolog‐deficient cells to poly(ADP‐ribose) polymerase inhibitor and Ara‐C mediated by 53BP1 loss and SAMHD1 overexpression

“…Although different PARPi, such as olaparib, rucaparib, niraparib and talazoparib, have similar PARP1 inhibition activity, they display differential capacity in trapping PARP1‐DNA complexes . Moreover, different from other PARPi, niraparib elicits its anticancer effects appearing in a manner of relatively low dependency on HR deficiency in either animal models or patients . However, current studies primarily focus on the resistance to only one PARPi, for example, olaparib.…”

“…1 Although different PARPi, such as olaparib, rucaparib, niraparib and talazoparib, have similar PARP1 inhibition activity, they display differential capacity in trapping PARP1-DNA complexes. 1,28 Moreover, different from other PARPi, niraparib elicits its anticancer effects appearing in a manner of relatively low dependency on HR deficiency in either animal models 29 or patients. 30 However, current studies primarily focus on the resistance to only one PARPi, for F I G U R E 5 Upregulation of SAMHD1 was associated with the resistance of poly(ADP-ribose) polymerase inhibitors (PARPi)-resistant variants to Ara-C. A, Cells were treated with the indicated drugs for 72 hours and then subjected to sulforhodamine B (SRB) assays.…”

PARP inhibitors in ovarian cancer: Sensitivity prediction and resistance mechanisms

“…49 In addition, RAD51C promoter methylation was demonstrated to be associated with PARP inhibitor response in a PDX model. 19 BCCIP is an important cofactor for BRCA2 in tumour suppres- | 2305 demonstrated to be significantly associated with in vitro PARP inhibitor sensitivity in a series of 39 ovarian cancer cell lines. 35 Whether PTEN deficiency causes HR deficiency (HRD) in the repair of DNA DSBs remains controversial.…”

“…92 The loss of Artemis, another critical factor in NHEJ, was found to be associated with resistance to niraparib in an HGSOC PDX model. 19 Thus, the synthetic lethality between PARP inhibition and HR deficiency requires the concomitant competence of the NHEJ pathway.…”

Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer

“…Class-switching in response to altered niche(s) during disease progression or chemotherapy was also captured [44][45][46][47] . These observations may align HGSC heterogeneity with distinct cells of origin by suggesting CCMand EMT-class tumors as molecularly distinct diseases that present class-specific therapeutic targets, besides improving our understanding of cellular and biological process in the DP-class ( Fig.7c; [48][49][50][51][52][53][54] . In conclusion, our study highlights two facets of drug resistance wherein intermediate cell states dynamically generate tumor heterogeneity, while slow-cycling epithelial cells are likely to be more resilient over other phenotypes.…”