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BackgroundAsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation.MethodsThe aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design.ResultsThe MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies.ConclusionThe dose of 600 mg was identified as the optimal dose for further clinical development.Clinical trial registrationClinical trial registration (NCT number): NCT03579628.

International audience; It is increasingly suggested that ecological and evolutionary sciences could inspire novel therapies against cancer but medical evidence of this remains scarce at the moment. The Achilles heel of conventional and targeted anticancer treatments is intrinsic or acquired resistance following Darwinian selection, i.e. treatment toxicity places the surviving cells under intense evolutionary selective pressure to develop resistance. Here, we review a set of data that demonstrate that Darwinian principles derived from the “smoke detector” principle can instead drive the evolution of malignant cells toward a different trajectory. Specifically, long term exposure of cancer cells to a strong alarm signal, generated by the DNA repair inhibitor AsiDNA, induces a stable new state characterized by a down‐regulation of the targeted pathways and does not generate resistant clones. This property is due to the original mechanism of action of AsiDNA, which acts by over‐activating a “false” signaling of DNA damage through DNA‐PK and PARP enzymes, and is not observed with classical DNA repair inhibitors such as the PARP inhibitors. Long‐term treatment with AsiDNA induces a new “alarm down” state in the tumor cells with decrease of NAD level and reactiveness to it. These results suggest that agonist drugs such as AsiDNA could promote a state‐dependent tumor cell evolution by lowering their ability to respond to high “danger” signal. This analysis provides a compelling argument that evolutionary ecology could help drug design development in overcoming fundamental limitation of novel therapies against cancer due to the modification of the targeted tumor cell population during treatment.

Purpose: Carboplatin is used to treat many cancers, but occurrence of drug resistance and its high toxicity remain a clinical hurdle limiting its efficacy. We compared the efficacy and toxicity of DNA repair inhibitors olaparib or AsiDNA administered alone or in combination with carboplatin. Olaparib acts by inhibiting PARP-dependent repair pathways whereas AsiDNA inhibits double-strand break repair by preventing recruitment of enzymes involved in homologous recombination and non-homologous end joining. Experimental Design: Mice with MDA-MB-231 tumors were treated with carboplatin or/and olaparib or AsiDNA for three treatment cycles. Survival and tumor growth were monitored. Toxicities of treatments were assayed in C57BL/6 immunocompetent mice. Circulating blood hematocrits, bone marrow cells, and organs were analyzed 10 and 21 days after end of treatment using flow cytometry and microscopy analysis. Resistance occurrence was monitored after cycles of treatments with combination of AsiDNA and carboplatin in independent BC227 cell cultures. Results: Olaparib or AsiDNA monotherapies decreased tumor growth and increased mean survival of grafted animals. The combination with carboplatin further increased survival. Carboplatin toxicity resulted in a decrease of most blood cells, platelets, thymus, and spleen lymphocytes. Olaparib or AsiDNA monotherapies had no toxicity, and their combination with carboplatin did not increase toxicity in the bone marrow or thrombocytopenia. All animals receiving carboplatin combined with olaparib developed high liver toxicity with acute hepatitis at 21 days. In vitro, carboplatin resistance occurs after three cycles of treatment in all six tested cultures, whereas only one became resistant (1/5) after five cycles when carboplatin was associated to low doses of AsiDNA. All selected carboplatin-resistant clones retain sensitivity to AsiDNA. Conclusion: DNA repair inhibitor treatments are efficient in the platinum resistant model, MDA-MB-231. The combination with carboplatin improves survival. The association of carboplatin with olaparib is associated with high liver toxicity, which is not observed with AsiDNA. AsiDNA could delay resistance to carboplatin without increasing its toxicity.

Purpose: Therapeutic strategies targeting DNA repair defects have been widely explored, but often restricted to a specific population of patients and tackled with resistance issues. We pioneered a new approach of anti-cancer treatment to tackle emergence of resistance: the decoy agonist mechanism of action. Drugs based on this mechanism hijack and hyperactivate therapeutic targets leading to an impairment of the repair signaling. This breakthrough decoy agonist action has already shown, using our lead compound AsiDNA™, target engagement, excellent safety profile in humans, and importantly lack of acquired resistance. Here, we describe mechanistically the immunomodulatory properties and metabolic effects of a new generation product OX401, generated using the proprietary PlatON™ platform of oligonucleotides designed to trap PARP proteins. Experimental design: OX401-induced PARP activation, NAD+ consumption and cell cytotoxicity were monitored using tumor and non-tumor cells. DNA repair abrogation was monitored by analyzing repair protein recruitment to damage sites. Accumulation of cytoplasmic DNA fragments was monitored after DNA staining and microscopy analysis. OX401 effect on the innate immune response was assessed by following STING pathway activation and T-cell mediated anti-tumor cytotoxicity. OX413, a “super” OX401 was designed to be more stable and less prone to intracellular enzymatic degradation. In a cell-derived xenograft model of mouse breast cancer, OX413-induced PARP activation and percentages of tumor-infiltrating leucocytes (CD45+: CD3+, CD8+, NK, DCs) were analyzed ex-vivo by flow cytometry. Results: Using different tumor models, we showed that OX401 binds and hyper-activates PARP1 with a high affinity and in a dose-dependent manner. As a consequence, OX401 impaired DNA repair due to PARP sequestration leading to an accumulation of cytoplasmic chromatin fragments (CCFs). In line with this, we demonstrated that OX401 displayed cell-autonomous immunomodulatory properties. Mechanistically, the generated CCFs triggered an innate immunity activation through cGAS/STING pathway, downstream CCL5 secretion and potentiation of the anti-tumor T-cell dependent immune response. Through PARP hyper-activation, OX401 also induced a rapid NAD+ consumption (below the viability threshold). This metabolic exhaustion caused selective tumor cell death while sparing healthy cells. These effects were enhanced using the optimized OX413 molecule, and at doses approximately 10 to 100-fold lower compared to OX401. In-vivo, OX413 triggered PARP1 target engagement and STING pathway activation, correlated to an increased innate and adaptive immune cells infiltration. Conclusions: Our results provide a preclinical rationale for using OX413 as an immunomodulatory and “metabolic exhauster” agent, especially in appropriately molecularly selected patients with tumors showing metabolic deficiencies. Citation Format: Wael Jdey, Christelle Zandanel, Véronique Trochon-Joseph, Chloé Doizelet, Vincent Hayes, Marie-Christine Lienafa, Richard Tripelon, Françoise Bono. A new generation of PARP interfering drug candidates for cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 527.

Purpose: PARP inhibitors (PARPi) resistance remains a major clinical hurdle as virtually all patients treated with PARPi will eventually relapse. We already demonstrated that co treatment with AsiDNA abrogates and reverses PARPi-acquired resistance. However, the mechanisms by which AsiDNA prevents genetic adaptations driving resistance and allows long-term efficacy of PARPi remain unknown. Here, we describe that PARPi resistance occurs through emergence of drug-tolerant cells (DTC) preventing PARPi from achieving long-term efficacy. Emerging evidence implicates a survival of residual DTC that constitutes a reservoir from which drug-resistant proliferative cells may emerge. We demonstrate in this study that AsiDNA is able to target specifically DTC and therefore represents a therapeutic opportunity to impede tumor relapse under PARPi treatment. Experimental design: AsiDNA is a double stranded (DS) DNA molecule (decoy oligonucleotide) that mimics DS DNA breaks to interfere with DNA repair, by over-activating a false DNA damage signaling through DNA-PK and PARP enzymes. We used different treatment protocols, cyclic or continuous, to select resistance to the PARPi Olaparib and Talazoparib and assessed the impact of AsiDNA addition on resistance abrogation, durability and irreversibility. We also addressed the mechanisms underlying the survival and evolution of the residual DTC under PARPi treatment, and how AsiDNA could impede their outgrowth. Results: Long-term treatment of BRCA2-mutated cells initially highly sensitive to PARPi leads to acquired resistance in all independently treated populations. Addition of AsiDNA to PARPi completely and irreversibly abolishes resistance emergence. This AsiDNA-dependent resistance abrogation is maintained for at least twelve weeks after AsiDNA removal (nine weeks after treatment start), indicating that AsiDNA maintains PARPi efficacy. PARPi-acquired resistance does not occur through selection of pre-existing BRCA2-wt and/or HR proficient sub-clones, but rather via (epi)-genetic evolution toward an active HR pathway and high genetic instability. We hypothesize that PARPi resistance occurs through a DTC stage as it is described for other targeted therapies like tyrosine kinase inhibitors (TKi). DTC are characterized by a transient senescent phenotype and evolve progressively into proliferative state. We showed that repeated treatments with PARPi lead to the apparition of a DTC-like population displaying a senescent phenotype evolving over time into proliferative cells. The co-treatment with AsiDNA and PARPi prevents DTC regrowth. Conclusion: Several groups have demonstrated that resistance to TKi can emerge from DTC. Our findings provide for the first time the evidence that PARPi-resistant cells can evolve from DTC, and point to the therapeutic opportunity of combining AsiDNA and PARPi to prevent or overcome resistance in clinical situation. Citation Format: Wael Jdey, Olivier Calvayrac, Orlane Maloudi, Florent Ubelmann, Gilles Favre, Françoise Bono. Acquired resistance to PARP inhibitors evolves from drug-tolerant cells vulnerable to AsiDNA [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4078.

Hematologic malignancies are rare cancers that develop refractory disease upon patient relapse, resulting in decreased life expectancy and quality of life. DNA repair inhibitors are a promising strategy to treat cancer but are limited by their hematologic toxicity in combination with conventional chemotherapies. Dbait are large molecules targeting the signaling of DNA damage and inhibiting all the double-strand DNA break pathways. Dbait have been shown to sensitize resistant solid tumors to radiotherapy and platinum salts. Here, we analyze the efficacy and lack of toxicity of AsiDNA, a cholesterol form of Dbait, in hematologic malignancies. We show that AsiDNA enters cells via LDL receptors and activates its molecular target, the DNA dependent protein kinase (DNA-PKcs) in 10 lymphoma and leukemia cell lines (Jurkat-E6.1, MT-4, MOLT-4, 174xCEM.T2, Sup-T1, HuT-78, Raji, IM-9, THP-1, and U-937) and in normal primary human PBMCs, resting or activated T cells, and CD34+ progenitors. The treatment with AsiDNA induced necrotic and mitotic cell death in most cancer cell lines and had no effect on blood or bone marrow cells, including immune activation, proliferation, or differentiation. Sensitivity to AsiDNA was independent of p53 status. Survival to combined treatment with conventional therapies (etoposide, cyclophosphamides, vincristine, or radiotherapy) was analyzed by isobolograms and combination index. AsiDNA synergized with all treatments, except vincristine, without increasing their toxicity to normal blood cells. AsiDNA is a novel, potent, and wide-range drug with the potential to specifically increase DNA-damaging treatment toxicity in tumor without adding toxicity in normal hematologic cells or inducing immune dysregulation. Mol Cancer Ther; 16(12); 2817–27. ©2017 AACR.

Melanomas are highly radioresistant tumors, mainly due to efficient DNA double-strand break (DSB) repair. Dbait (which stands for DNA strand break bait) molecules mimic DSBs and trap DNA repair proteins, thereby inhibiting repair of DNA damage induced by radiation therapy (RT). First, the cytotoxic efficacy of Dbait in combination with RT was evaluated in vitro in SK28 and 501mel human melanoma cell lines. Though the extent of RT-induced damage was not increased by Dbait, it persisted for longer revealing a repair defect. Dbait enhanced RT efficacy independently of RT doses. We further assayed the capacity of DT01 (clinical form of Dbait) to enhance efficacy of "palliative" RT (10 × 3 Gy) or "radical" RT (20 × 3 Gy), in an SK28 xenografted model. Inhibition of repair of RT-induced DSB by DT01 was revealed by the significant increase of micronuclei in tumors treated with combined treatment. Mice treated with DT01 and RT combination had significantly better tumor growth control and longer survival compared to RT alone with the "palliative" protocol [tumor growth delay (TGD) by 5.7-fold; median survival: 119 vs 67days] or the "radical" protocol (TGD by 3.2-fold; median survival: 221 vs 109days). Only animals that received the combined treatment showed complete responses. No additional toxicity was observed in any DT01-treated groups. This preclinical study provides encouraging results for a combination of a new DNA repair inhibitor, DT01, with RT, in the absence of toxicity. A first-in-human phase I study is currently under way in the palliative management of melanoma in-transit metastases (DRIIM trial).

The Achilles heel of conventional and targeted anticancer treatments is intrinsic or acquired resistance following Darwinian selection, i.e. treatment toxicity place the surviving cells under intense evolutionary selective pressure to develop resistance. Here, we demonstrate that AsiDNA, the first antitumor drug with an agonist activity, can instead drive the evolution of malignant cells toward a different trajectory. Specifically, long term exposure of cancer cells to the strong alarm signal, generated by the AsiDNATM DNA repair inhibitors, did not promote resistance emergence. It induces a stable new state characterized by the down regulation of the targeted pathways that persists for months after treatments. This property is due to the original mechanism of action of AsiDNATM, which acts by over-activating a “false” signaling of DNA damage through DNA-PK and PARP enzymes, and is not observed with other DNA repair inhibitors such as the PARP inhibitors olaparib and talazoparib. Transcriptomic analysis of AsiDNATM treated independent populations derived from lung and breast cancers revealed the common evolution of independent AsiDNA-treated samples, resulting in a general down-regulation of enzymes involved in DNA repair and oncogenesis, and a specific down regulation of DNA-PK targets. Similar down regulation of DNA-PK targets was observed in xenografted tumor in animal models after three cycles of AsiDNA treatment. Chromatin analysis revealed a major change in AsiDNATM treated populations with an increased nucleosome stability that could be responsible for the epigenetic modification observed. Long term treatment with AsiDNATM induces a new “alarm down” state in the tumor cells that increase its efficacy. These results suggest that agonist drugs such as AsiDNATM could promote a state-dependent tumor cell evolution by lowering their ability to respond to damage signal as predicted by the ecological and evolutionary “smoke detector principle”. Citation Format: Wael Jdey, Maria Kozlac, Sergey Alekseev, Danielle Johnson, françoise Bono, Srividya bhaskara, frederic thomas, Marie Dutreix. AsiDNATM, a targeted therapy with no acquired resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2095.

Therapeutic strategies targeting DNA repair pathway defects have been widely explored, but often only benefit small numbers of patients. Here we characterized potential predictive biomarkers for treatment with AsiDNA, a novel first-in-class DNA repair inhibitor. We evaluated genetic instability and DNA repair defects by direct and indirect assays in 12 breast cancer cell lines to estimate the spontaneous occurrence of single-strand and double-strand breaks (DSB). For each cell line, we monitored constitutive PARP activation, spontaneous DNA damage by alkaline comet assay, basal micronuclei levels, the number of large-scale chromosomal rearrangements (LST), and the status of several DNA repair pathways by transcriptome and genome analysis. Sensitivity to AsiDNA was associated with a high spontaneous frequency of cells with micronuclei and LST and specific alterations in DNA repair pathways that essentially monitor DSB repair defects. A high basal level of micronuclei as a predictive biomarker for AsiDNA treatment was validated in 43 tumor cell lines from various tissues and 15 models of cell- and patient-derived xenografts. Micronuclei quantification was also possible in patient biopsies. Overall, this study identified genetic instability as a predictive biomarker for sensitivity to AsiDNA treatment. That micronuclei frequency can be measured in biopsies and does not reveal the same genetic instability as conventional genome assays opens new perspectives for refining the classification of tumors with genetic instability. Cancer Res; 77(16); 4207–16. ©2017 AACR.

Purpose: The Achilles' heel of all conventional and targeted anticancer treatments is intrinsic or acquired resistance. The era of precision medicine where tumors are selected for specific treatments based on their genetic alterations is revolutionary, but unfortunately prolonged responses are rarely observed due to rapid emergence of resistant clones. We recently developed a new concept of DNA repair inhibitor (Dbait) acting by activating enzymes involved in DNA damage signaling. We tested how such agonist activity would be prone to induce resistance to Dbait treatment. Experimental design: We performed repeated cycles of treatment with various targeted therapy agents (Imatinib, Olaparib, 6-thioguanine and the clinical form of Dbait, AsiDNATM). We analyzed the specific sensitivity of independent cultures after each treatment cycle. The study was performed in different tumor cell lines ((MDAMB231, MDAMB468, HCC1143, THP1, U937, KBM7) and in two non-malignant breast cell lines (MCF10A, MCF12A). Extensive transcriptome and genome studies were performed on MDAMB231 breast cancer cell lines. Results: Resistant clones appeared at a frequency of 1.45% for Olaparib, 0.62% for imatinib, and 1.66% for 6-thioguanine. Similar protocol did not select for resistance to AsiDNA. Unexpectendly, tumor cells became more sensitive to AsiDNA after each cycle of treatment. This behavior was specific of AsiDNA and was not observed with other treatments. The six tumor cell lines tested developed AsiDNA autosensitisation and no resistance. Non tumoral cells were not affected by repeated treatments. The acquired sensitivity of the treated tumor populations was conserved for months after end of treatment Transcriptional and genetic analysis of independently treated MDAMB-231 populations reveals that all evolved similarly. They display a few conserved genome modifications and a large deregulation of 1160 genes resulting in an overexpression of luminal associated genes and a decrease in mesenchymal associated genes. Conclusion: Our results indicate a phenomenon of “autosensitisation”, along treatment which has never been described for anticancer treatment and could prevent development of resistance during treatment. Citation Format: Maria Kozlac, Wael Jdey, Pierre-Marie Girard, Françoise Bono, Marie Dutreix. The evolution of tumor cells under AsiDNA treatment results in “autosensitization” [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2851.

Purpose: while being registered and used in restricted subset of T-cell lymphoma, HDAC inhibitors (HDACi) have shown limited antitumor effect as single agents. Recent studies have shown an effect of HDACi on DNA damage accumulation, rationalizing their combination with DNA repair inhibitors. In the current study, we propose a novel therapeutic strategy, based on drug combination of HDACi with the pan-DNA break repair inhibitor AsiDNA to promote their antitumor activity. Experimental design: AsiDNATM is a double stranded DNA molecule (decoy oligo-nucleotide) that mimics double stranded DNA breaks (DSBs) to interfere with DNA repair, redirecting repair enzymes away from sites of tumor DNA damage. Belinostat is a pan-HDACi displaying a better safety profile compared to other HDACi. We characterized the effects of each drug on DNA break accumulation and genetic instability by γH2AX analysis, COMET assay and micronuclei detection. We further studied the antitumor efficacy of the combination of the two drugs. Finally, we assessed the effect of AsiDNA on the occurrence of acquired resistance after long term treatment with belinostat. Results: Molecular analyses of DNA damage after treatment demonstrate that belinostat paves the way for AsiDNA efficacy by inducing DNA DSBs as measured by γH2AX accumulation and tail moment increase on COMET assay. Moreover, continuous treatment with belinostat induced an increase of basal genetic instability in tumor cells measured by micronuclei accumulation, a prerequisite for AsiDNA antitumor efficacy1. On the other hand, AsiDNA enhances the effects of belinostat on histone acetylation, demonstrating a high potentiation of belinostat activity on its targets by AsiDNA. This mechanism-based cross-potentiation between AsiDNA and belinostat results in a high synergistic antitumor efficacy of the combined treatment in different tumor models. This synergistic effect was further confirmed with several HDACi belonging to different classes. Importantly, the combined treatment do not induce any DNA damage increase and/or lethality in non-tumor cells. Finally, repeated treatments allowed the emergence of resistance to belinostat, which is abrogated in presence of AsiDNA, indicating an unlikely tumor escape to this combined therapy. Conclusion: Altogether these results indicate a cross potentiation between AsiDNA and belinostat, and support the rational to investigate the clinical activity of this novel synergistic combination in different tumor types. As belinostat has obtained FDA conditional approval, and AsiDNA is already tested in a first-in-man clinical trial, a potential exists for a rapid clinical confirmation of the interest of this new combination. Citation Format: Wael Jdey, Hélène Toussaint, Coraline Cassegrain, Laura Bellassen, Richard Tripelon, Vincent Hayes, Perrine Pivette, Véronique Trochon-Joseph, Jean-Louis Labernardière, Marie Dutreix, Françoise Bono Colombie. AsiDNA and HDAC inhibitors: A cross-potentiation team working to kill tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2818.

Purpose: PARP inhibitors (PARPi) have shown significant benefits in cancer patients with BRCA mutations. However, their major limitations are the necessity of homologous recombination (HR) deficiency and the rapid emergence of resistance. In the current study, we propose a novel therapeutic strategy, based on drug combination to promote sensitivity to PARPi independently of the tumor genetics. Experimental design: We used AsiDNA, a DNA repair pathways agonist (Dbait concept), consisting in small molecules mimicking double-strand DNA breaks to activate ectopic signaling of DNA damage and prevent recruitment at damage sites of HR repair enzymes. We characterized the DNA repair inhibition activity of AsiDNA by monitoring repair foci formation and DNA damage and analyzed the cell survival to AsiDNA monotherapy and combination with the PARPi Olaparib of 21 tumor cell lines, and 3 non-tumor cell lines. Efficacy of the combination treatment was analyzed in tumor xenografts derived from the MDA-MB-231 cell line showing reduced sensitivity to AsiDNA and Olaparib in vitro. We screened for the frequency of clones resistant to two weeks treatment with AsiDNA or Olaparib in the 4NQO-mutagenized haploid KBM7 cells. Results: Molecular analyses of repair foci formed after irradiation demonstrate that AsiDNA inhibits recruitment of RAD51 and 53BP1 whereas Olaparib prevents XRCC1. Combination of both drugs increases the accumulation of unrepaired spontaneous damage resulting in an increase of cell death in all tumor cell lines. The synergy of the association of AsiDNA with PARPi was also confirmed with 6 other PARPi. AsiDNA do not induce any increase in DNA damage or lethality in non-tumor cells when used in monotherapy as well as in association with PARPi. Multi-omics analysis of tumor cells highlighted a correlation between similarity to normal cells profile and AsiDNA resistance. Selection of resistant clones allowed the emergence of resistance to Olaparib (1.45%), Imatinib (0.6%) and 6-Thioguanine (1.6%) but not to AsiDNA ( Conclusion: Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status. Moreover, the low frequency of appearance of resistant clones to AsiDNA suggests a sustained efficacy during treatment unlike most targeted therapies. Citation Format: marie DUTREIX, Wael Jdey, sylvain Thierry, Inna Kuperstein, Graham Dixon. AsiDNA induce tumor sensitivity to PARP inhibitors in homologous recombination proficient breast cancer AsiDNA induce tumor sensitivity to PARP inhibitors in homologous recombination proficient breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1110. doi:10.1158/1538-7445.AM2017-1110