In this new PNAS study,1 Pappas et al. uncover an entirely distinct mechanism: loss-of-function alterations in DNA pre-replication complex (pre-RC) genes — specifically CDT1, CDC6, and DBF4 — can drive PARPi resistance independently of BRCA2 reversion. Using functional genomics screens in BRCA2-deficient prostate cancer organoid models, the authors show that disrupting these replication licensing factors reduces replication stress, mitigates fork collapse, and circumvents the synthetic lethality normally exploited by PARPi.
Strikingly, clinical genomic data revealed copy number loss of pre-RC genes in approximately half of mCRPC cases, suggesting this mechanism is not rare. The authors also report that inhibiting the CDT1/geminin complex (e.g., with AF615) can re-sensitize resistant cells to PARPi, highlighting a potential therapeutic strategy.
Clinically, these findings broaden our view of PARPi resistance and identify pre-RC gene loss as a candidate worth exploring as a potential PARPi response biomarker. They also open the door to novel combination approaches to overcome resistance in BRCA-mutant prostate cancer. For practicing urologic oncologists, recognizing that resistance is not solely tied to BRCA reversions is key to guiding future clinical trial enrollment and precision therapy decisions.
Written by:
- Kyrie Pappas, PhD, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
- Charles L. Sawyers, MD, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY; HHMI, Chevy Chase, MD
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