Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors
Jinhyuk Bhin,
Mariana Paes Dias,
Ewa Gogola,
Frank Rolfs,
Sander R. Piersma,
Roebi de Bruijn,
Julian R. de Ruiter,
Bram van den Broek,
Alexandra A. Duarte,
Wendy Sol,
Ingrid van der Heijden,
Christina Andronikou,
Taina S. Kaiponen,
Lara Bakker,
Cor Lieftink,
Ben Morris,
Roderick L. Beijersbergen,
Marieke van de Ven,
Connie R. Jimenez,
Lodewyk F.A. Wessels,
Sven Rottenberg,
Jos Jonkers
Affiliations
Jinhyuk Bhin
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Department of Biomedical System Informatics, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
Mariana Paes Dias
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Ewa Gogola
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Frank Rolfs
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; OncoProteomics Laboratory, Department Medical Oncology, Amsterdam UMC, 1081HV Amsterdam, the Netherlands
Sander R. Piersma
OncoProteomics Laboratory, Department Medical Oncology, Amsterdam UMC, 1081HV Amsterdam, the Netherlands
Roebi de Bruijn
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Julian R. de Ruiter
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Bram van den Broek
Division of Cell Biology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Alexandra A. Duarte
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Wendy Sol
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Ingrid van der Heijden
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Christina Andronikou
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3088 Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Taina S. Kaiponen
Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3088 Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
Lara Bakker
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Cor Lieftink
Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Ben Morris
Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Roderick L. Beijersbergen
Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Marieke van de Ven
Mouse Clinic for Cancer and Aging, Preclinical Intervention Unit, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands
Connie R. Jimenez
OncoProteomics Laboratory, Department Medical Oncology, Amsterdam UMC, 1081HV Amsterdam, the Netherlands
Lodewyk F.A. Wessels
Division of Molecular Carcinogenesis, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Corresponding author
Sven Rottenberg
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Cancer Therapy Resistance Cluster and Bern Center for Precision Medicine, Department for Biomedical Research, University of Bern, 3088 Bern, Switzerland; Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland; Corresponding author
Jos Jonkers
Division of Molecular Pathology, Oncode Institute, the Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands; Corresponding author
Summary: 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 (PARPis), 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 combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.
