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LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin

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LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin Cancer Molecular and Cellular Pathobiology Research LRP1B Deletion in High-Grade Serous Ovarian Cancers Is Associated with Acquired Chemotherapy Resistance to Liposomal Doxorubicin Prue A. Cowin1,3,4, Joshy George1,5, Sian Fereday1, Elizabeth Loehrer1, Peter Van Loo6,7, Carleen Cullinane1,4, Dariush Etemadmoghadam1,4, Sarah Ftouni1, Laura Galletta1, Michael S. Anglesio8, Joy Hendley1, Leanne Bowes1, Karen E. Sheppard2,5, Elizabeth L. Christie1, Australian Ovarian Cancer Study1,9,11, Richard B. Pearson2,3,5, Paul R. Harnett10, Viola Heinzelmann-Schwarz12, Michael Friedlander13, Orla McNally14, Michael Quinn14, Peter Campbell6, Anna deFazio9, and David D.L. Bowtell1,3,4,5 Abstract High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from individual patients were analyzed along with 22 paired pretreatment and posttreatment samples. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients. Cancer Res; 72(16); 4060–73. Ó2012 AACR. Introduction Genomic change is a hallmark of tumor progression, associ- Authors' Affiliations: 1Cancer Genomics and Genetics Program, 2Onco- atedwithdefects incheckpointcontrol and DNA repair mechan- genic Signalling and Growth Control Program, Peter MacCallum Cancer isms (1, 2). Somatic mutations arising during tumor develop- Centre, Melbourne, Victoria; 3Sir Peter MacCallum Department of Oncol- ogy, Departments of 4Pathology and 5Biochemistry and Molecular Biology, ment generate intratumoral heterogeneity, which underlie The University of Melbourne, Parkville, Australia; 6Cancer Genome Project, within-patient differences in tumor morphology, growth, and Wellcome Trust Sanger Institute, Cambridge, United Kingdom; 7Depart- ment of Human Genetics, VIB and University of Leuven, Leuven, Belgium; therapeutic response. The degree of intratumoral heterogeneity 8University of British Columbia, BC Cancer Research Centre, Vancouver, is a reflection of mutation rate, emergence of clones with a British Columbia, Canada; 9Department of Gynaecological Oncology and selection benefit, and genetic drift in the population (3, 4). Westmead Institute for Cancer Research; 10Crown Princess Mary Cancer Centre Westmead and Westmead Institute for Cancer Research, University Intratumoral heterogeneity has been reported in a number of Sydney at Westmead Millennium Institute, Westmead Hospital, New of solid cancers, leukemia and lymphoma (5, 6), and has been 11 South Wales; Queensland Institute of Medical Research, Brisbane, identified by analysis of individual genes such as TP53 and Queensland; 12Ovarian Cancer Group, Lowy Cancer Research Centre, University of New South Wales, School of Women's and Children's ERBB2 (7), using single-nucleotide polymorphism (SNP; ref. 8) Health/Prince of Wales Clinical School; 13Prince of Wales Hospital, Rand- or microsatellite analysis (7) of a small number of loci. More wick, Sydney, New South Wales; and 14Department of Obstetrics and Gynaecology, Royal Women's Hospital, Parkville, Australia recently, complex DNA copy number microarrays and next- generation sequencing techniques have provided powerful Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). techniques for exploring clonal diversity, tumor evolution, and development of treatment resistance. For example, chromo- Corresponding Author: David D.L. Bowtell, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett St., Melbourne, Victoria, Australia somal structural information from next-generation sequenc- 3000. Phone: 61-3-9656-1356; Fax: 61-3-9656-1414; E-mail: ing has been used to track dispersal of pancreatic metastases to [email protected] different organs and estimate time course of disease (9, 10). doi: 10.1158/0008-5472.CAN-12-0203 Genomic variation has been observed between samples col- Ó2012 American Association for Cancer Research. lected at presentation and recurrence in breast cancer (11), 4060 Cancer Res; 72(16) August 15, 2012 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2012 American Association for Cancer Research. Analysis of Acquired Chemoresistance in Ovarian Cancer acute lymphoblastic leukemia (ALL; refs. 12, 13), and cervical collection of clinical data, pathologic review, and biospecimen cancer (14). Analysis of individual sectors of solid tumors, flow processing have been described previously (27). Details of cytometry sorting (8, 15, 16), and single-cell sequencing (17) primary surgical and paired pretreatment and relapse cohorts have identified distinct populations of tumor cells within are provided in Supplementary Methods. individual patient samples. These studies provide insight into rates of genomic change in an evolving cancer and, impor- Genomic analysis tantly, help define genes associated with tumor progression DNA and RNA samples were processed according to man- and treatment failure (18). ufacture's protocol for Affymetrix SNP6.0 Mapping arrays and Ovarian cancer is a histologically diverse disease, with high- Affymetrix GeneST 1.0 arrays, respectively. DNA copy number grade serous cancer (HGSC) accounting for approximately was obtained as described previously (19). Information on 65% of deaths. Most women with advanced HGSC are initially normalization and analysis is available in Supplementary responsive to treatment, but majority relapse with disease that Methods. DNA copy number and gene expression data are becomes progressively less responsive to chemotherapy (5). available at National Center for Biotechnology Information HGSC show considerable DNA copy number change (19), with (NCBI), Gene Expression Omnibus (GEO) accession numbers high rates of genomic instability (20) and somatic TP53 muta- GSE38787 and GSE38734, respectively. tion (21, 22). Intratumoral heterogeneity has been observed in Genomic distances between 2 tumor samples from the HGSC using microsatellite probes and SNP markers in cancer- same patient were determined by identifying regions of copy À associated genes (7). A study comparing loss of heterozygosity number change (Log20.3 and 0.3 for gains and losses, respec- patterns in primary and metastatic HGSC found a complex tively), where a contiguous genomic region was considered a rather than sequential pattern of clonal evolution (23). Selec- genome-altering event. The number of distinct genomic events tion of preexisting minor genetic subpopulations has been was considered the distance between any pair of genomes. Two associated with emergence of drug-resistant disease (5). genomic regions were considered distinct if, and only if, at least Several molecular events associated with emergence of one breakpoint was greater than a threshold (100,000 bps). treatment resistance in ovarian cancer have recently been Pairwise distance between samples were used to construct a identified. Intragenic BRCA1/2 mutations, resulting in partial phylogenetic tree for each individual using the "neighbor- restoration of defective germ line alleles, have been observed in joining" tree estimation (28). tumors following platinum-based chemotherapy and emer- gence of resistance (24). Cells lines derived from pre- and post- Quantitative real-time PCR treatment patient samples have identified HDAC-4–regulated Measurement of expression of coding genes was carried out STAT1 activation (25) and DNA-PK mediated activation of AKT using SYBR green quantitative real-time reverse transcriptase (26) as influencing sensitivity of HGSC to platins. Whether other PCR (qRT-PCR) assay (Applied Biosystems) as previously mechanisms exist to influence development of treatment resis- described (29). qRT-PCR conditions are provided in Supple- tance and how intratumoral heterogeneity relates to clinical mentary Methods. outcome in ovarian cancer remains to be explored. Here we examine spatial and temporal diversity in HGSC Cell culture, transfection, and drug sensitivity assays using high-resolution SNP arrays, multiple metastatic lesions IGROV1 and OVCAR4 cells were obtained from the National from individual patients, and paired pre- and posttreatment Cancer Institute Repository. Kuramochi cells from Japan
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