BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts

I Lohse; A Borgida; P Cao; M Cheung; M Pintilie; T Bianco; S Holter; E Ibrahimov; R Kumareswaran; R G Bristow; M-S Tsao; S Gallinger; D W Hedley

doi:10.1038/bjc.2015.220

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BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts

Journal article

Open access

Peer reviewed

BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts

I Lohse, A Borgida, P Cao, M Cheung, M Pintilie, T Bianco, S Holter, E Ibrahimov, R Kumareswaran, R G Bristow, …

British journal of cancer, Vol.113(3), pp.425-432

2015-07-28

DOI: https://doi.org/10.1038/bjc.2015.220

PMCID: PMC4522629

PMID: 26180923

Abstract

Humans

Male

Carcinoma, Pancreatic Ductal - genetics

Cisplatin - administration & dosage

Pancreatic Neoplasms - drug therapy

Genes, BRCA2

Germ-Line Mutation

Carcinoma, Pancreatic Ductal - mortality

Female

Pancreatic Neoplasms - mortality

Genes, BRCA1

Deoxycytidine - administration & dosage

Pancreatic Neoplasms - pathology

Pancreatic Neoplasms - genetics

Mice, SCID

Carcinoma, Pancreatic Ductal - pathology

Xenograft Model Antitumor Assays

Carcinoma, Pancreatic Ductal - drug therapy

Drug Resistance, Neoplasm - genetics

Animals

Antineoplastic Combined Chemotherapy Protocols - therapeutic use

Cell Line, Tumor

Mice, Inbred NOD

Mice

Deoxycytidine - analogs & derivatives

Germline mutations of the BRCA tumour suppressors have been associated with increased risk of pancreatic cancer. Clinical evidence suggests that these patients may be more sensitive to treatment with cisplatin. As the frequency of germline BRCA mutations is low, definitive experimental data to support the clinical observations are still missing. We tested gemcitabine and cisplatin sensitivity of four BRCA1 and BRCA2 mutant and three BRCA1 and BRCA2 wild-type (WT) patient-derived pancreatic cancer xenografts. We observed treatment sensitivity to gemcitabine and cisplatin in the BRCA WT and mutant models. The BRCA1 and BRCA2 mutant xenografts were significantly more sensitive to cisplatin although these models also showed sensitivity to gemcitabine. The BRCA1 and BRCA2 WT models showed sensitivity to gemcitabine but not cisplatin. Treatment sensitivity in the xenograft models closely resembled treatment response in the corresponding patients. We have characterised a panel of xenografts derived from pancreatic cancer patients carrying germline BRCA mutations, and shown that their genetic features resemble the patient donor. Our results support further clinical testing of treatment regimens combining gemcitabine and platinum drugs in this patient population, as well as preclinical research aiming to identify mechanisms of cisplatin resistance in BRCA mutant pancreatic cancers.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.151 Pancreas & Gall Bladder Disorders; 1.151.395 Pancreatic Cancer
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: BRCA1 and BRCA2 mutations sensitize to chemotherapy in patient-derived pancreatic cancer xenografts
Creators: I Lohse - Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9
A Borgida - Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9
P Cao - Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9
M Cheung - Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9
M Pintilie - Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9
T Bianco - 1] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9 Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9
S Holter - Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9
E Ibrahimov - 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9
R Kumareswaran - Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9
R G Bristow - Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9
M-S Tsao - 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 Department of Pathology, University Health Network, Toronto, Ontario, Canada M5G 2M9 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada M5G 2M9
S Gallinger - 1] Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, Toronto, Ontario, Canada M5G 2M9 Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9
D W Hedley - 1] Ontario Cancer Institute and Campbell Family Cancer Research Institute, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada M5G 2M9 Translational Research Initiative in Pancreas Cancer, Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 2M9 Department of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada M5G 2M9
Publication Details: British journal of cancer, Vol.113(3), pp.425-432
Academic Unit: Miller School of Medicine; UMMG Dept of Psychiatry & Behavioral Sciences
Language: English
Resource Type: Journal article
PMID: 26180923
PMCID: PMC4522629
Record Identifier: 991031599794102976