Abstract
BackgroundPoly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations.MethodsWe examined if olaparib, when combined with IgG1 antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab.ResultsNK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15Rα further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2; and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma.ConclusionsThese studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.
Highlights
(ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair
An ongoing phase 2 study of olaparib and the programmed death-ligand 1 (PD-L1) inhibitor durvalumab in metastatic castration-resistant prostate cancer patients demonstrated that 8/17 patients (47%) had a decrease in prostate-specific antigen (PSA) of > 50%, with two of those patients having no known mutations in DNA damage response pathways [2]
We focused on two prostate carcinoma cell lines, breast cancer susceptibility gene (BRCA) mutant 22RV1 and BRCA WT DU145; both were exposed to olaparib in vitro
Summary
(ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations. (ADP-ribose) polymerase inhibitors (PARPi) are FDA approved for use in ovarian and breast carcinoma with the mutant breast cancer susceptibility gene (BRCA). Data suggest that the mechanism of action in these tumors is synthetic lethality, wherein the PARP inhibitors block the recruitment of the requisite base excision DNA repair pathway machinery and defects in BRCA simultaneously prevent homologous recombination, leading to genomic instability. An ongoing phase 2 study of olaparib and the programmed death-ligand 1 (PD-L1) inhibitor durvalumab in metastatic castration-resistant prostate cancer (mCRPC) patients demonstrated that 8/17 patients (47%) had a decrease in prostate-specific antigen (PSA) of > 50%, with two of those patients having no known mutations in DNA damage response pathways [2]. It should be noted that the Fc region of durvalumab has been modified in such a way that it does not induce either antibody-dependent cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC)
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