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

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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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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Can PARP inhibitors be the holy grail for breast cancer treatment?

Oncology Times UK ◽

10.1097/01434893-200909000-00014 ◽

2009 ◽

Vol 6 (9) ◽

pp. 15-16

Author(s):

Robert H Carlson

Keyword(s):

Breast Cancer ◽

Cancer Treatment ◽

Parp Inhibitors ◽

Breast Cancer Treatment ◽

Holy Grail

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Adjuvant Breast Cancer Treatment and Cognitive Function: Current Knowledge and Research Directions

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/95.3.190 ◽

2003 ◽

Vol 95 (3) ◽

pp. 190-197 ◽

Cited By ~ 103

Author(s):

K.-A. Phillips ◽

J. Bernhard

Keyword(s):

Breast Cancer ◽

Cognitive Function ◽

Cancer Treatment ◽

Current Knowledge ◽

Breast Cancer Treatment ◽

Research Directions ◽

Adjuvant Breast Cancer

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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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Tamoxifen resistance mechanisms in breast cancer treatment

World Journal of Advanced Research and Reviews ◽

10.30574/wjarr.2020.5.2.0429 ◽

2020 ◽

Vol 8 (2) ◽

pp. 224-232

Author(s):

Asima Tayyeb

Keyword(s):

Breast Cancer ◽

Cancer Treatment ◽

Molecular Mechanisms ◽

Tamoxifen Resistance ◽

Resistance Mechanisms ◽

Breast Cancer Treatment ◽

Therapeutic Interventions ◽

Survival Outcomes ◽

Breast Cancer Patients ◽

Current Review

Therapies targeting estrogen receptor (ER) are being widely used to treat ER+ breast cancer patients. Despite early detection and improved survival outcomes, tamoxifen resistance, either intrinsic or acquired- is a major obstacle in effective disease management. Current review will summarize different molecular mechanisms of tamoxifen resistance both intrinsic and acquired in breast cancer treatment. This review not only provides basis to understand the nature of tamoxifen drug resistance but also suggests the mechanisms for its control leading to improved therapeutic interventions.

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Resistance to Intervention: Paclitaxel in Breast Cancer

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520999201214234421 ◽

2020 ◽

Vol 20 ◽

Author(s):

Vipin Mohan Dan ◽

Reji Saradha Raveendran ◽

Sabulal Baby

Keyword(s):

Breast Cancer ◽

Cancer Treatment ◽

Patient Outcomes ◽

Clinical Management ◽

Drug Targets ◽

Metastatic Cancer ◽

Resistance Mechanisms ◽

Breast Cancer Treatment ◽

Regulatory Proteins ◽

Oriented Research

Abstract:: Breast cancer stands as the most prevalent cancer in women globally, and contributes to highest percentage in mortality to cancer related deaths in women. Paclitaxel (PTX) is heavily relied on as a frontline chemotherapy in breast cancer treatment, especially in advanced metastatic cancer. Generation of resistance to PTX often derails clinical management and adversely affects patient outcomes. Defining the molecular mechanism underlying PTX resistance is mostly sought for to aid in overcoming resistance, and this oriented research has led to the understanding of a range of PTX resistance related therapeutic targets. PTX resistance pathways that involve major regulatory proteins/RNAs like RNF8/Twist/ROR1, TLR, ErbB3/ErbB2, BRCA1-IRIS, MENA, LIN9, MiRNA, FoxM1 and IRAK1 have expanded the complexity of resistance mechanisms, and brought newer insights for development of drug targets. This resistance related targets can be dealt with synthetic/natural therapeutics in combination with PTX. The present review encompasses recent understanding of PTX resistance mechanisms in breast cancer and possible therapeutic combinations to overcome resistance.

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PARP Inhibitors in Melanoma—An Expanding Therapeutic Option?

Cancers ◽

10.3390/cancers13184520 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4520

Author(s):

Wei Yen Chan ◽

Lauren J. Brown ◽

Lee Reid ◽

Anthony M. Joshua

Keyword(s):

Homologous Recombination ◽

Synthetic Lethality ◽

Checkpoint Inhibitors ◽

Therapeutic Option ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Brca Mutations ◽

Immune Priming ◽

Combination Strategies ◽

Damage Repair

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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