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

Bhin, J.; Paes Dias, M.; Gogola, E.; Rolfs, F.; Piersma, S. R.; de Bruijn, R.; de Ruiter, J.; van den Broek, B.; Duarte, A.; Sol, W.; van der Heijden, I.; Bakker, L.; Kaiponen, T. S.; Lieftink, C.; Morris, B.; Beijersbergen, R. L.; van de Ven, M.; Jimenez, C. R.; Wessels, L. F. A.; Rottenberg, S.; Jonkers, J.

doi:10.1101/2022.09.07.506927

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bioRxiv · 10.1101/2022.09.07.506927

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

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Abstract

BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR-defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi) but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combined molecular profiling with functional analysis of the HR status of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent functional restoration of BRCA1/2. We observed restoration of HR in 64% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we found that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by the loss of PARG. Our combined multi-omics analysis catalogued additional genes and pathways potentially involved in modulating PARPi response.

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Bhin, J., Paes Dias, M., Gogola, E., Rolfs, F., Piersma, S. R., de Bruijn, R., de Ruiter, J., van den Broek, B., Duarte, A., Sol, W., van der Heijden, I., Bakker, L., Kaiponen, T. S., Lieftink, C., Morris, B., Beijersbergen, R. L., van de Ven, M., Jimenez, C. R., Wessels, L. F. A., Rottenberg, S., Jonkers, J.. 2022-09-07. Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors. https://doi.org/10.1101/2022.09.07.506927

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