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The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance.

ABSTRACT:

Abstract

The use of poly(ADP-ribose) polymerase inhibitor (PARPi) exploits synthetic lethality in solid tumors with homologous recombination repair (HRR) defects. Significant clinical benefit has been established in breast and ovarian cancers harboring BRCA1/2 mutations, as well as tumors harboring characteristics of "BRCAness." However, the durability of treatment responses is limited, and emerging data have demonstrated the clinical challenge of PARPi resistance. With the expanding use of PARPi, the significance of PARP therapy in patients pretreated with PARPi remains in need of significant further investigation. Molecular mechanisms contributing to this phenomenon include restoration of HRR function, replication fork stabilization, BRCA1/2 reversion mutations, and epigenetic changes. Current studies are evaluating the utility of combination therapies of PARPi with cell cycle checkpoint inhibitors, antiangiogenic agents, phosphatidylinositol 3-kinase/AKT pathway inhibitors, MEK inhibitors, and epigenetic modifiers to overcome this resistance. In this review, we address the mechanisms of PARPi resistance supported by preclinical models, examine current clinical trials applying combination therapy to overcome PARPi resistance, and discuss future directions to enhance the clinical efficacy of PARPi.

SUBMITTER: Pham MM

PROVIDER: S-EPMC9255699 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single-strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation-associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCA-deficient breast and ovarian cancer. Because of phenotypic similarities between some "triple-negative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients.

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The Clinical Challenges, Trials, and Errors of Combatting Poly(ADP-Ribose) Polymerase Inhibitors Resistance.

Abstract

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