Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair

“…Their data suggest that the underlying defect is the impaired single-strand annealing, a DSB repair pathway that involves both BRCA1 and EXO1 (van de Kooij et al, 2024 ). Interestingly, they did not report a similar dependence of BRCA2-deficient cells on EXO1, which is consistent with our findings (Bhin et al, 2023 ) that demonstrate distinct capacities of BRCA1- and BRCA2-deficient cells in restoring HR. Consistent with their data, our study also reveals an increased sensitivity of PARG-proficient BRCA1;p53-deficient cells to LNT1.…”

“…For this screen, we introduced an inducible Cas9 system into the KB2P cells. After the lentiviral transduction with the YUSA library and subsequent selection with puromycin, Cas9 expression was induced with doxycyline for 2 days, and cells were collected as reference (day 0) or propagated for 15 days, either in a DMSO-control condition or in the presence of the PARG inhibitor PDDX-004 (James et al, 2016 ; Waszkowycz et al, 2018 ), which effectively inhibits mouse PARG (Gogola et al, 2018 ; Bhin et al, 2023 ). For the screen, we applied 100 nM of PDDX-004, a concentration that conferred olaparib resistance and MMS-induced increase in PARylation levels of KB2P cells (Fig.…”

“…In the era of precision medicine, this may provide useful information to guide future clinical trials. (2) Based on our unique genetically engineered mouse models to study PARPi resistance in BRCA1/2 -mutated tumors, we expect that PARG loss may be a mechanism of secondary resistance that is selected out when patients receive continuous, daily PARPi treatment, e.g., as maintenance therapy (Gogola et al, 2018 ; Bhin et al, 2023 ). Although the relevance of this mechanism still needs to be validated using second biopsies of patient tumors that initially responded and eventually became drug resistant, our data support the use of EXO1/FEN1 inhibitors to counteract resistance mediated by PARG loss.…”

“…Nevertheless, secondary BRCA1/2 mutations explain only some of the PARPi cases (Ang et al, 2013 ; Tobalina et al, 2021 ; Baxter et al, 2022 ). In our recent work, we have found that PARG loss is the most frequently detected PARPi-resistance mechanism in mammary tumors from BRCA2-deficient triple-negative breast cancer (TNBC) mouse models (Gogola et al, 2018 ; Bhin et al, 2023 ). Mechanistically, we uncovered that PARG loss mediates PARPi resistance by partially restoring PARP1 signaling, and we observed that biopsies of TNBC and high serous ovarian carcinoma patients carry a substantial percentage of tumor cells with low expression of PARG and increased PARylation (Gogola et al, 2018 ).…”

C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer

“…Although PARPi in combination with chemotherapy have been approved for management of BRCA-associated metastatic triple-negative breast cancer (TNBC) 1 , 2 , benefits are not durable with almost universal recurrence. The mechanisms underlying PARPi resistance have been explored extensively and include BRCA1/2 reversion mutations, hypomorphic BRCA1/2 alleles, loss of hypermethylation of BRCA1/2, loss of the shieldin complex and activation of pro-survival pathways such as the MAPK and PI3K pathways 3 – 7 . However, taken together, the identified mechanisms can only explain PARPi resistance in a subset of patients 8 – 10 .…”