The evolving landscape of predictive biomarkers of response to PARP inhibitors
Anish Thomas, … , Junko Murai, Yves Pommier
Anish Thomas, … , Junko Murai, Yves Pommier
Published April 16, 2018
Citation Information: J Clin Invest. 2018;128(5):1727-1730. https://doi.org/10.1172/JCI120388.
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Commentary

The evolving landscape of predictive biomarkers of response to PARP inhibitors

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPis) are DNA-damaging agents that trap PARP-DNA complexes and interfere with DNA replication. Three PARPis — olaparib, niraparib, and rucaparib — were recently approved by the FDA for the treatment of breast and ovarian cancers. These PARPis, along with 2 others (talazoparib and veliparib), are being evaluated for their potential to treat additional malignancies, including prostate cancers. While lack of PARP-1 confers high resistance to PARPis, it has not been established whether or not the levels of PARP-1 directly correlate with tumor response. In this issue of the JCI, Makvandi and coworkers describe an approach to address this question using [18F]FluorThanatrace, an [18F]-labeled PARP-1 inhibitor, for PET. The tracer was taken up by patient tumor tissue and appeared to differentiate levels of PARP-1 expression; however, future studies should be aimed at determining if this tracer can be used to stratify patient response to PARPi therapy.

Authors

Anish Thomas, Junko Murai, Yves Pommier

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Figure 1

Clinical PARP inhibitors (PARPis) and determinants of response and resistance to PARPis.

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Clinical PARP inhibitors (PARPis) and determinants of response and resis...
(A) Three PARPis are approved for ovarian and/or breast cancers. All PARPis comprise a nicotinamide moiety (red), which binds the β-NAD+ acceptor site in PARP-1 and PARP-2. PARPis differ by their PARP-trapping potency. (B) PARPis are potential substrates for the drug efflux pumps (PgP/ABCB1), which limit cellular accumulation. Binding of the PARPis to the NAD+ site of PARP-1 and PARP-2 (red circle) results both in catalytic inhibition by competitive inhibition of β-NAD+ binding and in PARP trapping by a proposed reverse allosteric mechanism (5). Trapping can be mitigated by increased PARP-1 and PARP-2 auto-PARylation due to high NAD+ synthesis by nicotinamide phosphoribosyltransferase (NAMPT) or enhanced by PAR removal by poly(ADP-ribose) glycohydrolase (PARG). Trapping of PARP-1 and PARP-2 damages replicating cells. Cells can alleviate this effect by stabilizing replication forks through BRCA2 and other factors of the Fanconi anemia pathway (FANC) or suppression of the polycomb complex (EZH2). Damaged cells can also repair the broken forks by homologous recombination (HR) involving BRCA1 or BRCA2 or commit themselves to death through Schlafen 11 (SLFN11). Inactivation of 53BP1 and REV7 reactivates HR. Red symbols define determinants of response to the PARPis. Blue symbols signify resistance to PARPis. Synthetic lethality (4) occurs in cancer cells deficient for the resistance factors highlighted in blue. BRCA1 and BRCA2 were the first resistance factors identified and led to the approval of PARPis as monotherapy.