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Eliminating hypoxic tumor cells improves response to PARP inhibitors in homologous recombination-deficient cancer models.

ABSTRACT: Hypoxia, a hallmark feature of the tumor microenvironment, causes resistance to conventional chemotherapy, but was recently reported to synergize with poly(ADP-ribose) polymerase inhibitors (PARPis) in homologous recombination-proficient (HR-proficient) cells through suppression of HR. While this synergistic killing occurs under severe hypoxia (<0.5% oxygen), our study shows that moderate hypoxia (2% oxygen) instead promotes PARPi resistance in both HR-proficient and -deficient cancer cells. Mechanistically, we identify reduced ROS-induced DNA damage as the cause for the observed resistance. To determine the contribution of hypoxia to PARPi resistance in tumors, we used the hypoxic cytotoxin tirapazamine to selectively kill hypoxic tumor cells. We found that the selective elimination of hypoxic tumor cells led to a substantial antitumor response when used with PARPi compared with that in tumors treated with PARPi alone, without enhancing normal tissue toxicity. Since human breast cancers with BRAC1/2 mutations have an increased hypoxia signature and hypoxia reduces the efficacy of PARPi, then eliminating hypoxic tumor cells should enhance the efficacy of PARPi therapy.

SUBMITTER: Mehibel M

PROVIDER: S-EPMC8266208 | biostudies-literature |

REPOSITORIES: biostudies-literature

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PARP inhibitors for homologous recombination-deficient prostate cancer.

Project description:INTRODUCTION:Prostate adenocarcinoma represents a leading cause of cancer-related mortality. Increased emphasis on understanding the molecular basis of prostate cancer has identified a substantial burden of homologous recombination (HR) pathway mutations, which are enriched in castrate-resistant disease. This discovery has yielded novel therapeutic opportunities. Areas covered: We will discuss the treatment of castrate-resistant prostate cancer (CRPC), with a focus on the use of poly (ADP-ribose) polymerase (PARP) inhibitors in this space. Evidence for use in HR-deficient patients will be outlined with discussion of the mechanism of action for this drug class, pathways of resistance, and approaches for expanding PARP inhibitor use to non-HR-deficient prostate cancer subgroups. Expert opinion: PARP inhibition represents an exciting tool for management of HR-inactivated CRPC. With rapid adoption of next-generation sequencing technologies and other molecular techniques, the number of patients in this category is likely to increase. Ongoing and future investigations will be critical for improved understanding of the promise and appropriate treatment sequencing of PARP inhibition and optimal options for HR-proficient and -deficient prostate cancer populations. Questions remain about the clinical significance of monoallelic vs. biallelic HR mutations, the relevance of germline vs. somatic-only mutations, and the importance of mutations in non-canonical HR genes.

| S-EPMC6088797 | biostudies-literature

Clinical use and mechanisms of resistance for PARP inhibitors in homologous recombination-deficient cancers.

Project description:Cells are continuously subjected to DNA damaging agents. DNA damages are repaired by one of the many pathways guarding genomic integrity. When one or several DNA damage pathways are rendered inefficient, cells can accumulate mutations, which modify normal cellular pathways, favoring abnormal cell growth. This supports malignant transformation, which can occur when cells acquire resistance to cell cycle checkpoints, apoptosis, or growth inhibition signals. Mutations in genes involved in the repair of DNA double strand breaks (DSBs), such as BRCA1, BRCA2, or PALB2, significantly increase the risk of developing cancer of the breast, ovaries, pancreas, or prostate. Fortunately, the inability of these tumors to repair DNA breaks makes them sensitive to genotoxic chemotherapies, allowing for the development of therapies precisely tailored to individuals' genetic backgrounds. Unfortunately, as with many anti-cancer agents, drugs used to treat patients carrying a BRCA1 or BRCA2 mutation create a selective pressure, and over time tumors can become drug resistant. Here, we detail the cellular function of tumor suppressors essential in DNA damage repair pathways, present the mechanisms of action of inhibitors used to create synthetic lethality in BRCA carriers, and review the major molecular sources of drug resistance. Finally, we present examples of the many strategies being developed to circumvent drug resistance.

| S-EPMC7847957 | biostudies-literature

WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors.

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| S-EPMC6830099 | biostudies-literature

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

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| S-EPMC5370566 | biostudies-literature

Arsenic compound sensitizes homologous recombination proficient ovarian cancer to PARP inhibitors.

Project description:The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors show survival benefits in ovarian cancer patients with BRCA1/2 mutation or homologous recombination (HR) deficiency, but only limited efficacy in HR-proficient ones. Another drug, arsenic trioxide (ATO) or arsenic drug (RIF), exerts antitumor effects via inducing DNA damage. Here, we investigated the combined therapeutic effects of the PARP inhibitors and the arsenic compound in HR-proficient ovarian cancer. The combined treatment of niraparib, olaparib, or fluazolepali with ATO showed a significant suppression in tumor cell viability and colony formation. The drug treatment also induced synergistic inhibition of cell proliferation and DNA damage, and acceleration of cell apoptosis in two HR-proficient ovarian cancer cell lines SKOV3 and CAOV3, either by simultaneous or sequential administration. The mechanism underlying these synergistic effects were reflected by the significantly increased ratio of cleaved-PARP/total PARP and decreased ratio of p-AKT/total AKT. Consistently, the combination of olaparib with RIF synergistically reduced the tumor growth in mouse xenograft models. In conclusion, the arsenic compound greatly sensitizes HR-proficient ovarian cancer cells to the PARP inhibitors, and our findings provide an evidence for the clinical treatment development of this combination in HR-proficient ovarian cancer patients.

| S-EPMC8458481 | biostudies-literature

ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells.

Project description:The response to poly(ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication-associated DNA damage, increased PARP trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers.

| S-EPMC7880902 | biostudies-literature

Progression through mitosis promotes PARP inhibitor-induced cytotoxicity in homologous recombination-deficient cancer cells.

Project description:Mutations in homologous recombination (HR) genes BRCA1 and BRCA2 predispose to tumorigenesis. HR-deficient cancers are hypersensitive to Poly (ADP ribose)-polymerase (PARP) inhibitors, but can acquire resistance and relapse. Mechanistic understanding how PARP inhibition induces cytotoxicity in HR-deficient cancer cells is incomplete. Here we find PARP inhibition to compromise replication fork stability in HR-deficient cancer cells, leading to mitotic DNA damage and consequent chromatin bridges and lagging chromosomes in anaphase, frequently leading to cytokinesis failure, multinucleation and cell death. PARP-inhibitor-induced multinucleated cells fail clonogenic outgrowth, and high percentages of multinucleated cells are found in vivo in remnants of PARP inhibitor-treated Brca2-/-;p53-/- and Brca1-/-;p53-/- mammary mouse tumours, suggesting that mitotic progression promotes PARP-inhibitor-induced cell death. Indeed, enforced mitotic bypass through EMI1 depletion abrogates PARP-inhibitor-induced cytotoxicity. These findings provide insight into the cytotoxic effects of PARP inhibition, and point at combination therapies to potentiate PARP inhibitor treatment of HR-deficient tumours.

| S-EPMC5520019 | biostudies-literature

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies.

Project description:As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single-strand or double-strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or, after a latency period, cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. Although the application of PARP inhibitors (PARPis) initially focused on tumors with BRCA1 or BRCA2 deficiencies, synthetic susceptibilities to PARPis have been expanded due to the identification of tumors with mutations pathways involved in DNA damage repair, in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder cancer and especially prostate cancer, contain subsets of patients with germline and somatic alterations in HR genes that may reflect an increased response to PARPis. In this review, the authors describe the mechanisms and rationale of the use of PARPis in patients with GU cancers, summarize previously reported preclinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can have widespread application in patients with GU cancers. Cancer 2017;123:1912-1924. © 2017 American Cancer Society.

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PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers.

Project description:Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP's role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field's progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

| S-EPMC6517993 | biostudies-literature

Nonhomologous end joining drives poly(ADP-ribose) polymerase (PARP) inhibitor lethality in homologous recombination-deficient cells.

Project description:Poly(ADP-ribose) polymerase (PARP) inhibitors are strikingly toxic to cells with defects in homologous recombination (HR). The mechanistic basis for these findings is incompletely understood. Here, we show that PARP inhibitor treatment induces phosphorylation of DNA-dependent protein kinase substrates and stimulates error-prone nonhomologous end joining (NHEJ) selectively in HR-deficient cells. Notably, inhibiting DNA-dependent protein kinase activity reverses the genomic instability previously reported in these cells after PARP inhibition. Moreover, disabling NHEJ by using genetic or pharmacologic approaches rescues the lethality of PARP inhibition or down-regulation in cell lines lacking BRCA2, BRCA1, or ATM. Collectively, our results not only implicate PARP1 catalytic activity in the regulation of NHEJ in HR-deficient cells, but also indicate that deregulated NHEJ plays a major role in generating the genomic instability and cytotoxicity in HR-deficient cells treated with PARP inhibitors.

| S-EPMC3044391 | biostudies-literature

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