Abstract 2934: Characterizing response to PARP inhibitor treatment combinations in advanced prostate cancer.

Cancer Research · 2026-04-03

Abstract Background: Combining poly (ADP-ribose) polymerase inhibitors (PARPi) with androgen receptor pathway inhibitors (ARPi) has improved advanced prostate cancer management but questions remain including 1) where in the clinical treatment paradigm will these combinations fare best? 2) what underlies the efficacy of these combinations? and 3) what else may be more effective in combination with a PARPi? Here, we address these questions to advance the utility of PARP inhibition. Methods: LNCaP (CSPC), C4-2B (CRPC), MDVR (enzalutamide-resistant C4-2B derivative), and AbiR (abiraterone-resistant C4-2B derivative) served as models of different advanced prostate cancer indications. Viability assays, microscopy, western blots and RNA-sequencing were used to investigate response to treatment. Results: Data suggest prior exposure to an ARPi does not preclude benefit from combination treatment, but that the effect is greatest in ARPi-naïve cells. Despite a decrease in cellular viability, morphology of treated cells reveals a largely cytostatic response. Transcriptomic analysis and western blots suggest current hypotheses explaining the mechanism of combination efficacy may be incomplete, as findings do not support that ARPis induce significant BRCAness nor that PARPis reduce AR activity. Given that PARPi and ARPi combination may be less effective post ARPi exposure, we sought an alternative which may be more effective in this setting. Our work suggests that PARPis induce a robust, ATM-driven DNA damage response, and that co-targeting ATM elicits a synergistic reduction in cellular viability. Co-inhibition of ATM and PARP is much more effective than ARPi containing combinations in models of ARPi-resistant CRPC. Conclusions: Current results suggest that 1) PARPi and ARPi combinations may be most effective earlier in the treatment paradigm, 2) more work is needed to understand PARPi and ARPi combination efficacy, and 3) ATM inhibition may be better in combination with a PARPi in more advanced settings. Future efforts will be directed at better understanding how these drugs work together and when best to administer them given the rapidly evolving prostate cancer treatment landscape. Citation Format: Bryan Correa Gonzalez, Akshaya Karthikeyan, Love A. Moore, Ethan Sandoval, Anamitra Bhuamik, Marion Hardy, Alan P. Lombard. Characterizing response to PARP inhibitor treatment combinations in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2934.

Figure S2 from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells

2026-03-16

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Figure S4 from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells

2026-03-16

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Figure S1 from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells

2026-03-16

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Characterizing Response to PARP Inhibitor Treatment Combinations in Advanced Prostate Cancer

Biomedicines · 2026-04-22

Background/Objectives: Combinations of PARP inhibitors (PARPi) and androgen receptor pathway inhibitors (ARPi) have led to clinical success in treating advanced prostate cancer. However, it is unclear where in the clinical paradigm these combinations will fare best, and their mechanism of action remains unclear. We sought to address open questions and explore alternative strategies to enhance PARPi efficacy. Methods: Viability and morphology were assessed in response to (1) abiraterone, olaparib, or combination and (2) enzalutamide, talazoparib, or combination in castration-resistant C4-2B cells and abiraterone- or enzalutamide-resistant derivative cell models (ARPi-resistant). The efficacy of the ATM inhibitor lartesertib with and without a PARPi was also determined. Western blots and RNA-sequencing were used to interrogate the mechanistic effects of treatment. Results: PARPi and ARPi combinations were effective in all models but provided the most benefit in ARPi-sensitive C4-2B cells. Mechanistically, ARPi was not found to affect homologous recombination repair gene expression but may increase PARP activity. Prolonged PARP inhibition was found to increase the expression of AR target genes, and PARPi pre-treatment increased sensitivity to enzalutamide. ATM inhibition significantly increases PARPi efficacy and appears to outperform ARPi-containing combinations in ARPi-resistant models. Conclusions: PARPi and ARPi combinations are effective in ARPi-resistant models, but efficacy appears stronger in ARPi-sensitive CRPC cells. Presented findings support a novel hypothesis that PARP inhibition may increase ARPi sensitivity with increasing AR activity. Additionally, ATM inhibition may provide more benefit than an ARPi in combination with a PARPi in ARPi-resistant settings. These findings support continued PARPi development for improving patient outcomes.

Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer

Molecular Cancer Therapeutics · 2026-04-09

Resistance to PARP inhibitors (PARPi) remains a major challenge in the treatment of advanced prostate cancer. Although metabolic rewiring has been implicated in this process, the molecular drivers and therapeutic vulnerabilities underlying this adaptation remain poorly defined. We integrated transcriptomic, functional, and clinical analyses to identify mitochondrial regulators of PARPi resistance. RNA sequencing and gene set enrichment analysis revealed robust enrichment of oxidative phosphorylation pathways in PARPi-resistant prostate cancer cells, with consistent upregulation of NDUFS4, a nuclear-encoded subunit of electron transport chain complex I. Elevated NDUFS4 expression correlated with poor survival in patient cohorts from TCGA and SU2C/PCF. Functional analyses demonstrated that genetic knockdown of NDUFS4 impaired complex I activity, reduced mitochondrial mass, and re-sensitized resistant cells to olaparib. Pharmacologic targeting of NDUFS4 using the niclosamide analog ARVib-7 phenocopied genetic depletion, suppressing mitochondrial respiration and enhancing olaparib efficacy to inhibit the growth of resistant spheroids. Both NDUFS4 silencing and ARVib-7 treatment induced ferroptotic stress, as evidenced by intracellular iron accumulation and altered expression of ferroptosis-associated markers including COX2, CHAC1, NRF2, and GPX4. These findings identify NDUFS4 as a key mediator of PARPi resistance and a therapeutic vulnerability in advanced prostate cancer. Targeting NDUFS4 disrupts oxidative phosphorylation and induces ferroptosis, providing a strong rationale for combination strategies with PARP inhibitors to overcome drug resistance.

Figure S5 from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells

2026-03-16

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Abstract 7129: Targeting PARPi drug tolerant persistence and progression on treatment with clinical stage ATM inhibitors in advanced prostate cancer

Cancer Research · 2026-04-03

Abstract Background: PARP inhibitors (PARPi) have improved prostate cancer management, but progression is inevitable. Drug tolerant persistence (DTP) is characterized by tumor cells which survive treatment and drive failure through transient acquisition of insensitivity. Cycling DTP cells may adapt and expand, giving rise to drug tolerant expanded persister (DTEP) populations which are thought to model progression on treatment. Emerging evidence supports a critical role for DTP in promoting PARPi progression. Identifying and targeting DTP and DTEP vulnerabilities may provide therapeutic strategies to combat disease progression. Methods: Viability assays, western blots, and additional assays defined treatment response in PARPi-sensitive C4-2B metastatic castration-resistant prostate cancer cells and C4-2B abiraterone-resistant derivative AbiR cells. DTP and DTEP models were developed through prolonged PARPi exposure. NGS profiled DTP cells. Clinical stage ATM inhibitors were tested for their effects on both DTP and DTEP populations. Results: Response to PARP inhibition is heterogeneous, characterized by cell death and emergence of a largely cytostatic, persistent population. C4-2B and AbiR cells exposed to clinically relevant PARPi dosing for 9 days followed by drug holiday regain normal, parental cell morphology and become re-sensitized to treatment in line with acquisition of a DTP phenotype. DTP cells display differential sensitivity to other classes of drugs compared to parental cells. DTP cells may be broadly stratified into two classes; 1) a minority which cycle and 2) those which don’t. Prolonged PARPi treatment is observed to result in drug tolerant expanded persisters (DTEP) derived from cycling-DTP cells. DTP and DTEP cells display increased phospho-ATM levels suggesting constitutive DNA damage response activation. Utilization of clinical stage ATM inhibitors both prevent DTP progression into DTEPs and resensitize DTEPs to PARP inhibition. Conclusions: Our data suggest that drug tolerant persistence may mediate survival of tumor cells which drive progression on treatment. ATM inhibition may be used to prolong time to progression or to treat progressive disease. Future studies will focus on translating these strategies. Citation Format: Akshaya Karthikeyan, Bryan Correa Gonzalez, Jose G. Torres-Gonzalez, Love A. Moore, Anamitra Bhaumik, Ethan Sandoval, Alan P. Lombard. Targeting PARPi drug tolerant persistence and progression on treatment with clinical stage ATM inhibitors in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7129.

Figure S3 from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells

2026-03-16

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Figure S1 from PINK1-Mediated Mitochondrial Activity Confers Olaparib Resistance in Prostate Cancer Cells

2025-04-03

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