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

Lee, Elizabeth K.; Matulonis, Ursula A.

doi:10.3390/cancers12082054

Cited by 50 publications

(67 citation statements)

References 177 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The best approach would be to implement treatment that would prevent the appearance of drug-resistant clones. There is a number of ongoing trials evaluating the efficacy of combinations of PARPi with other drugs[ 34 , 54 ]. Several studies demonstrated the potentially curative impact of high-dose chemotherapy for BRCA1/2 mutation carriers; however, the use of this treatment is associated with excessive adverse effects[ 55 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Imyanitov¹,

Sokolenko²

2021

WJCO

View full text Add to dashboard Cite

Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene. Consequently, BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly (ADP-ribose) polymerase inhibitors (PARPi). Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations, which restore the open-reading frame of the affected allele. This platinum/PARPi cross-resistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies. There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance; however, their actual clinical relevance remains to be established. In addition, studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells. These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure, but become outcompeted by BRCA1-deficient cells during therapy holidays. Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches, which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.

show abstract

Section: Discussionmentioning

confidence: 99%

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Imyanitov¹,

Sokolenko²

2021

WJCO

View full text Add to dashboard Cite

show abstract

“…Several mechanisms have been proposed such as alterations in PARP1 leading to increase in PARP1 catalytic activity or removal of PARP trapping, restoration of HRR via BRCA reversion mutations or demethylation of BRCA promoter as reviewed by Lee and Matulonis. [137] It is anticipated that the number of patients that are resistant to PARPis will continue to rise and thus it is critical to understand the mechanisms of PARPi resistance for optimizing treatment strategies such as targeted combination therapy. [137] In summary, several PARPis have been approved as therapeutic and maintenance therapy for multiple cancer types, typically based on the presence of germline or somatic BRCA PVs.…”

Section: Therapeutic Implications For Icismentioning

confidence: 99%

Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology

Shah

Demidova

Lesh

et al. 2022

Cancer Treatment Reviews

View full text Add to dashboard Cite

DNA repair vulnerabilities are present in a significant proportion of cancers. Specifically, germline alterations in DNA repair not only increase cancer risk but are associated with treatment response and clinical outcomes. The therapeutic landscape of cancer has rapidly evolved with the FDA approval of therapies that specifically target DNA repair vulnerabilities. The clinical success of synthetic lethality between BRCA deficiency and poly(ADPribose) polymerase (PARP) inhibition has been truly revolutionary. Defective mismatch repair has been validated as a predictor of response to immune checkpoint blockade associated with durable responses and long-term benefit in many cancer patients. Advances in next generation sequencing technologies and their decreasing cost have supported increased genetic profiling of tumors coupled with germline testing of cancer risk genes in patients. The clinical adoption of panel testing for germline assessment in high-risk individuals has generated a plethora of genetic data, particularly on DNA repair genes. Here, we highlight the therapeutic relevance of germline aberrations in DNA repair to identify patients eligible for precision treatments such as PARP inhibitors (PARPis), immune checkpoint blockade, chemotherapy, radiation therapy and combined treatment. We also discuss emerging mechanisms that regulate DNA repair.

show abstract

“…Resistance to PARP inhibitors is an active area of research and reviewed in detail elsewhere [47][48][49]. Briefly, the main proposed mechanisms of resistance to PARP inhibitors include restoration of homologous recombination activity (e.g., by reactivation of BR-CAm through secondary mutations), altered PARP expression, increased efflux of PARP inhibitors from cells, and stabilization of stalled replication forks (thereby reducing doublestrand breaks).…”

Section: Implications For Clinical Practicementioning

confidence: 99%

Maintenance Treatment of Newly Diagnosed Advanced Ovarian Cancer: Time for a Paradigm Shift?

DiSilvestro

Colombo

Harter

et al. 2021

Cancers

View full text Add to dashboard Cite

Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a BRCA1 and/or BRCA2 mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.

show abstract

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

Cited by 50 publications

References 177 publications

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

Therapeutic implications of germline vulnerabilities in DNA repair for precision oncology

Maintenance Treatment of Newly Diagnosed Advanced Ovarian Cancer: Time for a Paradigm Shift?

Contact Info

Product

Resources

About