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PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer.

ABSTRACT: PARP inhibitors were recently approved for treatment of molecularly-defined subsets of metastatic castrate-resistant prostate cancer (mCRPC) patients. Although the PARP inhibitor olaparib was approved for use in patients with a mutation in one of fourteen genes, the mutation frequency of the genes varies widely in mCRPC and the impact of the less commonly altered genes on PARP inhibitor sensitivity is uncertain. We used functional approaches to directly test the impact of PALB2 and BARD1 loss on homologous recombination (HR) function and PARP inhibitor sensitivity in prostate cancer cell lines. PALB2 or BARD1 loss led to decreased HR function as measured by loss of radiation-induced Rad51 foci formation as well as decreased HR capacity in a cell-based reporter assay. PALB2 or BARD1 loss also significantly increased sensitivity to the PARP inhibitors olaparib and rucaparib across a panel of prostate cancer cell lines. These data support PALB2 and BARD1 loss as markers of clinically relevant PARP inhibitor sensitivity and highlight the potential to use functional approaches to complement and extend findings from clinical trials of targeted agents.

SUBMITTER: Dillon KM

PROVIDER: S-EPMC9242979 | biostudies-literature |

REPOSITORIES: biostudies-literature

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ID3 promotes homologous recombination via non-transcriptional and transcriptional mechanisms and its loss confers sensitivity to PARP inhibition.

Project description:The inhibitor of DNA-binding 3 (ID3) is a transcriptional regulator that limits interaction of basic helix-loop-helix transcription factors with their target DNA sequences. We previously reported that ID3 loss is associated with mutational signatures linked to DNA repair defects. Here we demonstrate that ID3 exhibits a dual role to promote DNA double-strand break (DSB) repair, particularly homologous recombination (HR). ID3 interacts with the MRN complex and RECQL helicase to activate DSB repair and it facilitates RAD51 loading and downstream steps of HR. In addition, ID3 promotes the expression of HR genes in response to ionizing radiation by regulating both chromatin accessibility and activity of the transcription factor E2F1. Consistently, analyses of TCGA cancer patient data demonstrate that low ID3 expression is associated with impaired HR. The loss of ID3 leads to sensitivity of tumor cells to PARP inhibition, offering new therapeutic opportunities in ID3-deficient tumors.

| S-EPMC8599806 | biostudies-literature

ID3 Promotes Homologous Recombination via Non-transcriptional and Transcriptional Mechanisms and its Loss Confers Sensitivity to PARP Inhibition

2022-02-17 | PXD028946 | Pride

Targeting MALAT1 Augments Sensitivity to PARP Inhibition by Impairing Homologous Recombination in Prostate Cancer.

Project description:PARP inhibitors (PARPi) have emerged as a promising targeted therapeutic intervention for metastatic castrate-resistant prostate cancer (mCRPC). However, the clinical utility of PARPi is limited to a subset of patients who harbor aberrations in the genes associated with the homologous recombination (HR) pathway. Here, we report that targeting metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an oncogenic long noncoding RNA (lncRNA), contrives a BRCAness-like phenotype, and augments sensitivity to PARPi. Mechanistically, we show that MALAT1 silencing reprograms the homologous recombination (HR) transcriptome and makes prostate cancer cells more vulnerable to PARPi. Particularly, coinhibition of MALAT1 and PARP1 exhibits a decline in clonogenic survival, delays resolution of γH2AX foci, and reduces tumor burden in mice xenograft model. Moreover, we show that miR-421, a tumor suppressor miRNA, negatively regulates the expression of HR genes, while in aggressive prostate cancer cases, miR-421 is sequestered by MALAT1, leading to increased expression of HR genes. Conclusively, our findings suggest that MALAT1 ablation confers sensitivity to PARPi, thus highlighting an alternative therapeutic strategy for patients with castration-resistant prostate cancer (CRPC), irrespective of the alterations in HR genes.SignificancePARPi are clinically approved for patients with metastatic CRPC carrying mutations in HR genes, but are ineffective for HR-proficient prostate cancer. Herein, we show that oncogenic lncRNA, MALAT1 is frequently overexpressed in advanced stage prostate cancer and plays a crucial role in maintaining genomic integrity. Importantly, we propose a novel therapeutic strategy that emphasizes MALAT1 inhibition, leading to HR dysfunction in both HR-deficient and -proficient prostate cancer, consequently augmenting their susceptibility to PARPi.

| S-EPMC10561629 | biostudies-literature

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

Correlation of homologous recombination deficiency induced mutational signatures with sensitivity to PARP inhibitors and cytotoxic agents.

Project description:BackgroundHomologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction.ResultsUsing whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity.ConclusionOur results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.

| S-EPMC6857305 | biostudies-literature

WIP1 Promotes Homologous Recombination and Modulates Sensitivity to PARP Inhibitors.

Project description:Genotoxic stress triggers a combined action of DNA repair and cell cycle checkpoint pathways. Protein phosphatase 2C delta (referred to as WIP1) is involved in timely inactivation of DNA damage response by suppressing function of p53 and other targets at chromatin. Here we show that WIP1 promotes DNA repair through homologous recombination. Loss or inhibition of WIP1 delayed disappearance of the ionizing radiation-induced 53BP1 foci in S/G2 cells and promoted cell death. We identify breast cancer associated protein 1 (BRCA1) as interactor and substrate of WIP1 and demonstrate that WIP1 activity is needed for correct dynamics of BRCA1 recruitment to chromatin flanking the DNA lesion. In addition, WIP1 dephosphorylates 53BP1 at Threonine 543 that was previously implicated in mediating interaction with RIF1. Finally, we report that inhibition of WIP1 allowed accumulation of DNA damage in S/G2 cells and increased sensitivity of cancer cells to a poly-(ADP-ribose) polymerase inhibitor olaparib. We propose that inhibition of WIP1 may increase sensitivity of BRCA1-proficient cancer cells to olaparib.

| S-EPMC6830099 | biostudies-literature

PALB2 self-interaction controls homologous recombination.

Project description:PALB2 is essential for BRCA2 anchorage to nuclear structures and for homologous recombinational repair of DNA double-strand breaks. Here, we report that the N-terminal coiled-coil motif of PALB2 regulates its self-association and homologous recombination. Monomeric PALB2 shows higher efficiency to bind DNA and promotes RAD51 filament formation with or without the inhibitory effect of Replication Protein A. Moreover, overexpression of the PALB2 coiled-coil domain severely affects RAD51 loading to DNA damage sites suggesting a competition between PALB2 self-interaction and PALB2-BRCA1 interaction. In the presence of DNA damage, the switch between PALB2-PALB2 and PALB2-BRCA1 interactions allows the activation of HR. Controlling HR via PALB2 self-interactions could be important to prevent aberrant recombination in normal conditions and activate DNA repair when required.

| S-EPMC3488246 | biostudies-literature

PARP Inhibition in Prostate Cancer With Homologous Recombination Repair Alterations.

Project description:PurposeWith the broad use of next-generation sequencing assays, it has become clear that mutations in DNA repair genes are more commonly found than previously reported. In advanced prostate cancer patients with BRCA1/2 or ATM mutations, poly (ADP-ribose) polymerase inhibition (PARPi) causes an increased overall survival advantage compared with patients without these mutations. This review explores the advantages and limitations of PARPi treatment and its use beyond BRCA1/2-altered tumors. Furthermore, it discusses the benefits of current biomarkers and what role functional biomarkers and organoids may play in addressing the involvement of homologous recombination repair mutations in tumor development and progression.MethodsA systematic review was conducted in MEDLINE, National Library of Medicine, and ClinicalTrials.gov to identify studies published between January 1, 2016, and August 31, 2021. The search strategy incorporated terms for PARPi, BRCA, DNA damage, homologous recombination, organoids, patient-derived organoids, biomarker AND prostate cancer, breast cancer, ovarian cancer.ResultsA total of 261 records remained after duplicate removal, 69 of which were included in the qualitative synthesis.ConclusionTo improve the outcome of targeted therapy and increase sensitivity of tumor detection, patients should be repeatedly screened for DNA repair gene alterations and biomarkers. Future clinical studies should explore the use of PARPi beyond BRCA1/2 mutations and focus on finding new synthetically lethal interactions.

| S-EPMC8547927 | biostudies-literature

RNF19A-mediated ubiquitination of BARD1 prevents BRCA1/BARD1-dependent homologous recombination.

Project description:BRCA1-BARD1 heterodimers act in multiple steps during homologous recombination (HR) to ensure the prompt repair of DNA double strand breaks. Dysfunction of the BRCA1 pathway enhances the therapeutic efficiency of poly-(ADP-ribose) polymerase inhibitors (PARPi) in cancers, but the molecular mechanisms underlying this sensitization to PARPi are not fully understood. Here, we show that cancer cell sensitivity to PARPi is promoted by the ring between ring fingers (RBR) protein RNF19A. We demonstrate that RNF19A suppresses HR by ubiquitinating BARD1, which leads to dissociation of BRCA1-BARD1 complex and exposure of a nuclear export sequence in BARD1 that is otherwise masked by BRCA1, resulting in the export of BARD1 to the cytoplasm. We provide evidence that high RNF19A expression in breast cancer compromises HR and increases sensitivity to PARPi. We propose that RNF19A modulates the cancer cell response to PARPi by negatively regulating the BRCA1-BARD1 complex and inhibiting HR-mediated DNA repair.

| S-EPMC8599684 | biostudies-literature

<i>ATM</i> Loss Confers Greater Sensitivity to ATR Inhibition Than PARP Inhibition in Prostate Cancer.

Project description:Alterations in DNA damage response (DDR) genes are common in advanced prostate tumors and are associated with unique genomic and clinical features. ATM is a DDR kinase that has a central role in coordinating DNA repair and cell-cycle response following DNA damage, and ATM alterations are present in approximately 5% of advanced prostate tumors. Recently, inhibitors of PARP have demonstrated activity in advanced prostate tumors harboring DDR gene alterations, particularly in tumors with BRCA1/2 alterations. However, the role of alterations in DDR genes beyond BRCA1/2 in mediating PARP inhibitor sensitivity is poorly understood. To define the role of ATM loss in prostate tumor DDR function and sensitivity to DDR-directed agents, we created a series of ATM-deficient preclinical prostate cancer models and tested the impact of ATM loss on DNA repair function and therapeutic sensitivities. ATM loss altered DDR signaling, but did not directly impact homologous recombination function. Furthermore, ATM loss did not significantly impact sensitivity to PARP inhibition but robustly sensitized to inhibitors of the related DDR kinase ATR. These results have important implications for planned and ongoing prostate cancer clinical trials and suggest that patients with tumor ATM alterations may be more likely to benefit from ATR inhibitor than PARP inhibitor therapy. SIGNIFICANCE: ATM loss occurs in a subset of prostate tumors. This study shows that deleting ATM in prostate cancer models does not significantly increase sensitivity to PARP inhibition but does sensitize to ATR inhibition.See related commentary by Setton and Powell, p. 2085.

| S-EPMC7272301 | biostudies-literature

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