PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Immunotherapy has transformed the treatment landscape of melanoma; however, despite improvements in patient outcomes, monotherapy can often lead to resistance and tumour escape. Therefore, there is a need for new therapies, combination strategies and biomarker-guided decision making to increase the subset of patients most likely to benefit from treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors act by synthetic lethality to target tumour cells with homologous recombination deficiencies such as BRCA mutations. However, the application of PARP inhibitors could be extended to a broad range of BRCA-negative cancers with high rates of DNA damage repair pathway mutations, such as melanoma. Additionally, PARP inhibition has the potential to augment the therapeutic effect of immunotherapy through multi-faceted immune-priming capabilities. In this review, we detail the immunological role of PARP and rationale for combining PARP and immune checkpoint inhibitors, with a particular focus on a subset of melanoma with homologous recombination defects that may benefit most from this targeted approach. We summarise the biology supporting this combined regimen and discuss preclinical results as well as ongoing clinical trials in melanoma which may impact future treatment.

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Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00557-3 ◽

2021 ◽

Vol 53 (1) ◽

pp. 42-51

Author(s):

Dae-Seok Kim ◽

Cristel V. Camacho ◽

W. Lee Kraus

Keyword(s):

Clinical Trials ◽

Homologous Recombination ◽

Cancer Cells ◽

Synthetic Lethality ◽

Parp Inhibitor ◽

Cancer Therapeutics ◽

Progression Free Survival ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Combination Strategies

AbstractHomologous recombination (HR) repair deficiency impairs the proper maintenance of genomic stability, thus rendering cancer cells vulnerable to loss or inhibition of DNA repair proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1). Inhibitors of nuclear PARPs are effective therapeutics for a number of different types of cancers. Here we review key concepts and current progress on the therapeutic use of PARP inhibitors (PARPi). PARPi selectively induce synthetic lethality in cancer cells with homologous recombination deficiencies (HRDs), the most notable being cancer cells harboring mutations in the BRCA1 and BRCA2 genes. Recent clinical evidence, however, shows that PARPi can be effective as cancer therapeutics regardless of BRCA1/2 or HRD status, suggesting that a broader population of patients might benefit from PARPi therapy. Currently, four PARPi have been approved by the Food and Drug Administration (FDA) for the treatment of advanced ovarian and breast cancer with deleterious BRCA mutations. Although PARPi have been shown to improve progression-free survival, cancer cells inevitably develop resistance, which poses a significant obstacle to the prolonged use of PARP inhibitors. For example, somatic BRCA1/2 reversion mutations are often identified in patients with BRCA1/2-mutated cancers after treatment with platinum-based therapy, causing restoration of HR capacity and thus conferring PARPi resistance. Accordingly, PARPi have been studied in combination with other targeted therapies to overcome PARPi resistance, enhance PARPi efficacy, and sensitize tumors to PARP inhibition. Moreover, multiple clinical trials are now actively underway to evaluate novel combinations of PARPi with other anticancer therapies for the treatment of PARPi-resistant cancer. In this review, we highlight the mechanisms of action of PARP inhibitors with or without BRCA1/2 defects and provide an overview of the ongoing clinical trials of PARPi. We also review the current progress on PARPi-based combination strategies and PARP inhibitor resistance.

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PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Cancers ◽

10.3390/cancers12082054 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2054

Author(s):

Elizabeth K. Lee ◽

Ursula A. Matulonis

Keyword(s):

Synthetic Lethality ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Resistance Mechanisms ◽

Parp Inhibition ◽

Combination Therapies ◽

Mechanisms Of Resistance ◽

Damage Repair ◽

Inhibitor Resistance

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

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Frequency and prognostic value of mutations associated with the homologous recombination DNA repair pathway in a large pan cancer cohort

Scientific Reports ◽

10.1038/s41598-020-76975-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Daniel R. Principe ◽

Matthew Narbutis ◽

Regina Koch ◽

Ajay Rana

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Synthetic Lethality ◽

Parp Inhibitors ◽

The Cancer Genome Atlas ◽

Parp Inhibition ◽

Repair Pathway ◽

Wide Range ◽

Recombination Pathway ◽

Pan Cancer

AbstractPARP inhibitors have shown remarkable efficacy in the clinical management of several BRCA-mutated tumors. This approach is based on the long-standing hypothesis that PARP inhibition will impair the repair of single stranded breaks, causing synthetic lethality in tumors with loss of high-fidelity double-strand break homologous recombination. While this is now well accepted and has been the basis of several successful clinical trials, emerging evidence strongly suggests that mutation to several additional genes involved in homologous recombination may also have predictive value for PARP inhibitors. While this notion is supported by early clinical evidence, the mutation frequencies of these and other functionally related genes are largely unknown, particularly in cancers not classically associated with homologous recombination deficiency. We therefore evaluated the mutation status of 22 genes associated with the homologous recombination DNA repair pathway or PARP inhibitor sensitivity, first in a pan-cancer cohort of 55,586 patients, followed by a more focused analysis in The Cancer Genome Atlas cohort of 12,153 patients. In both groups we observed high rates of mutations in a variety of HR-associated genes largely unexplored in the setting of PARP inhibition, many of which were associated also with poor clinical outcomes. We then extended our study to determine which mutations have a known oncogenic role, as well as similar to known oncogenic mutations that may have a similar phenotype. Finally, we explored the individual cancer histologies in which these genomic alterations are most frequent. We concluded that the rates of deleterious mutations affecting genes associated with the homologous recombination pathway may be underrepresented in a wide range of human cancers, and several of these genes warrant further and more focused investigation, particularly in the setting of PARP inhibition and HR deficiency.

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Moving beyond PARP Inhibition: Current State and Future Perspectives in Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22157884 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7884

Author(s):

Michela Palleschi ◽

Gianluca Tedaldi ◽

Marianna Sirico ◽

Alessandra Virga ◽

Paola Ulivi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Treatment ◽

Synthetic Lethality ◽

Current Knowledge ◽

Parp Inhibitors ◽

Resistance Mechanisms ◽

Breast Cancer Treatment ◽

Parp Inhibition ◽

Combination Strategies ◽

Pubmed Search

Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms “PARP inhibitors” and “breast cancer”, was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.

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Landscape of homologous recombination deficiencies in solid tumours: analyses of two independent genomic datasets

BMC Cancer ◽

10.1186/s12885-021-09082-y ◽

2022 ◽

Vol 22 (1) ◽

Author(s):

Zhongwu Lai ◽

Matthew Brosnan ◽

Ethan S. Sokol ◽

Mingchao Xie ◽

Jonathan R. Dry ◽

...

Keyword(s):

Homologous Recombination ◽

Checkpoint Inhibitors ◽

Parp Inhibitors ◽

The Cancer Genome Atlas ◽

Future Research ◽

Allelic Loss ◽

Similar Degree ◽

Precision Oncology ◽

Sequencing Data ◽

Brca Mutations

Abstract Background DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types. Methods Germline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different candidate homologous recombination repair (HRR) genes, and their relationship with the genetic events of bi-allelic loss, loss of heterozygosity (LOH) and tumour mutation burden (TMB). Results Approximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations, identifying potentially 50% more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types. Conclusions Our results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.

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The DNA Damaging Revolution: PARP Inhibitors and Beyond

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_238473 ◽

2019 ◽

pp. 185-195 ◽

Cited By ~ 46

Author(s):

Timothy A. Yap ◽

Ruth Plummer ◽

Nilofer S. Azad ◽

Thomas Helleday

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Synthetic Lethality ◽

Checkpoint Inhibitors ◽

Parp Inhibitors ◽

Therapeutic Benefit ◽

Cytotoxic Agents ◽

Parp Inhibition ◽

Breast Cancers ◽

Trial Testing

Cancer-specific DNA repair defects are abundant in malignant tissue and present an opportunity to capitalize on these aberrations for therapeutic benefit. Early preclinical data demonstrated the concept of synthetic lethality between BRCA genetic defects and pharmacologic PARP inhibition, suggesting that there may be monotherapy activity with this class of agents and supporting the early trial testing of this molecularly driven approach. Although the first foray into the clinic for PARP inhibitors was in combination with DNA-damaging cytotoxic agents, clinical development was limited by the more-than-additive toxicity, in particular dose-limiting myelosuppression. As more tolerable single agents, PARP inhibitors are now approved for the treatment of ovarian cancer in different settings and BRCA-mutant breast cancers. Beyond PARP inhibitors, there is now a large armamentarium of potent and relatively selective inhibitors in clinical trial testing against key targets involved in the DNA damage response (DDR), including ATR, ATM, CHK1/2, WEE1, and DNA-PK. These agents are being developed for patients with molecularly selected tumors and in rational combinations with other molecularly targeted agents and immune checkpoint inhibitors. We detail the clinical progress made in the development of PARP inhibitors, review rational combinations, and discuss the development of emerging inhibitors against novel DDR targets, including DNA repair proteins, DNA damage signaling, and DNA metabolism.

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Targeting DNA Damage Repair for Immune Checkpoint Inhibition: Mechanisms and Potential Clinical Applications

Frontiers in Oncology ◽

10.3389/fonc.2021.648687 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wei Sun ◽

Qing Zhang ◽

Runkun Wang ◽

Yang Li ◽

Yue Sun ◽

...

Keyword(s):

Dna Damage ◽

Immune Checkpoint ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Dna Damage Repair ◽

Predictive Biomarkers ◽

High Sensitivity ◽

Parp Inhibitors ◽

Combination Strategies ◽

Damage Repair

DNA damage repair (DDR) pathways play an essential role in maintaining genomic integrity. DDR dysfunction leads to accumulated DNA damage, predisposition to cancer, and high sensitivity to chemotherapy and radiotherapy. Recent studies have demonstrated that DDR status is associated with response to immune checkpoint inhibitors (ICIs). Among the DDR pathways, mismatch repair is one of the most recognized predictive biomarkers for ICIs. Furthermore, preclinical and early clinical studies suggest the rationale of combining agents targeting the DDR pathways, such as poly (ADP-ribose) polymerase (PARP) inhibitors, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, and ataxia telangiectasia and rad3-related (ATR) kinase inhibitors, with ICIs. In the present review, we describe the predictive role of DDR pathways in ICIs and summarize the advances in potential combination strategies of novel agents targeting DDR with ICIs for cancer treatment.

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The Role of PARP Inhibitors in the Treatment of Prostate Cancer: Recent Advances in Clinical Trials

Biomolecules ◽

10.3390/biom11050722 ◽

2021 ◽

Vol 11 (5) ◽

pp. 722

Author(s):

Mingyue Xia ◽

Zhigang Guo ◽

Zhigang Hu

Keyword(s):

Prostate Cancer ◽

Drug Resistance ◽

Synthetic Lethality ◽

Adenosine Diphosphate ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Castration Resistant Prostate Cancer ◽

Brca Mutations ◽

Combination Treatments ◽

Bet Inhibitors

Poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPis) belong to a class of targeted drugs developed for the treatment of homologous recombination repair (HRR)-defective tumors. Preclinical and limited clinical data suggest that PARP inhibition is effective against prostate cancer (PC) in patients with HRR-deficient tumors and that PARPis can improve the mortality rate of PC in patients with BRCA1/2 mutations through a synthetic lethality. Olaparib has been approved by the FDA for advanced ovarian and breast cancer with BRCA mutations, and as a maintenance therapy for ovarian cancer after platinum chemotherapy. PARPis are also a new and emerging clinical treatment for metastatic castration-resistant prostate cancer (mCRPC). Although PARPis have shown great efficacy, their widespread use is restricted by various factors, including drug resistance and the limited population who benefit from treatment. It is necessary to study the combination of PARPis and other therapeutic agents such as anti-hormone drugs, USP7 inhibitors, BET inhibitors, and immunotherapy. This article reviews the mechanism of PARP inhibition in the treatment of PC, the progress of clinical research, the mechanisms of drug resistance, and the strategies of combination treatments.

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Genomic landscape of non-small cell lung cancer (NSCLC) with methylthioadenosine phosphorylase (MTAP) deletion.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9116 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9116-9116

Author(s):

Stephen L. Graziano ◽

Dean C. Pavlick ◽

Ethan Sokol ◽

Shakti H. Ramkissoon ◽

Eric Allan Severson ◽

...

Keyword(s):

Tumor Cell ◽

Synthetic Lethality ◽

Checkpoint Inhibitors ◽

Large Cell ◽

Combination Strategies ◽

Genomic Landscape ◽

Comprehensive Genomic Profiling ◽

Tumor Mutational Burden ◽

Cell Expression ◽

The Impact

9116 Background: NSCLC remains a major cause of cancer-associated mortality despite major advancements in treatments. In addition to immune checkpoint inhibitors (ICPI), new strategies for clinically advanced NSCLC now include the development of new synthetic lethality targets focused on protein arginine methyl transferases such as PRMT5 that exploit the impact of tumor cell genomic loss of MTAP. Methods: 29,379 advanced/metastatic NSCLC cases underwent hybrid-capture based comprehensive genomic profiling to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. PD-L1 tumor cell expression was determined by DAKO 22C3 immunohistochemistry (IHC); low positive was a tumor proportion score (TPS) 1-49% and high positive was a TPS ≥50%. Results: 3,928 NSCLC exhibited MTAP homozygous loss. Cases had the following subtypes: adenocarcinoma (59%), squamous cell ca (22%), NSCLC NOS (16%), and large cell neuroendocrine, sarcomatoid, adenosquamous ca (all 1%). GA/tumor were similar when CDKN2A/B losses associated with 9p21 co-deletion with MTAP loss are excluded. Significant differences in currently targetable GA included KRAS G12C higher in MTAP-intact NSCLC (P =.0003) and EGFR short variant mutations higher in MTAP-deleted NSCLC (P <.0001). MTAP-intact NSCLC had higher frequencies of GAs in TP53 (P <.0001) and RB1 and a lower frequency of SMARCA4 (P <.0001). GAs frequencies in ERBB2, MET, ALK, ROS1 and NTRK1 were similar. Biomarkers for potential ICPI efficacy were higher in MTAP-intact including TMB ≥10mut/Mb (P =.0002) and low and high PD-L1 IHC staining (P =.01). Biomarkers potentially predictive of ICPI resistance ( STK11 and KEAP1) were similar in both groups. Conclusions: MTAP loss occurs in 13% of NSCLC, supporting the development of novel targeted therapies designed to exploit PRMT5 hyper-dependence in these tumors. MTAP loss in NSCLC is accompanied by differences in targeted and ICPI options for these patients which may impact future combination strategies. Further study of anti-PRMT5 drugs that are enabled by MTAP loss in NSCLC appears warranted.[Table: see text]

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Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

BioMed Research International ◽

10.1155/2016/2346585 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 18

Author(s):

Stephen Murata ◽

Catherine Zhang ◽

Nathan Finch ◽

Kevin Zhang ◽

Loredana Campo ◽

...

Keyword(s):

Synthetic Lethality ◽

Parp Inhibitor ◽

Advanced Ovarian Cancer ◽

Parp Inhibitors ◽

Damage Repair ◽

Trial Testing ◽

United States Food ◽

States Food ◽

And Personalized Medicine ◽

Inhibitor Treatment

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use inBRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents inBRCAand non-BRCA-mutated cancers.

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