LRP1B deletion in high-grade serous ovarian cancers is associated with acquired chemotherapy resistance to liposomal doxorubicin.
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 Genomics and Genetics Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Prue A
PA
Cowin
Joshy
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George
Sian
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Fereday
Elizabeth
E
Loehrer
Peter
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Van Loo
Carleen
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Cullinane
Dariush
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Etemadmoghadam
Sarah
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Ftouni
Laura
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Galletta
Michael S
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Anglesio
Joy
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Hendley
Leanne
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Bowes
Karen E
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Sheppard
Elizabeth L
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Christie
Richard B
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Pearson
Paul R
PR
Harnett
Viola
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Heinzelmann-Schwarz
Michael
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Friedlander
Orla
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McNally
Michael
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Quinn
Peter
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Campbell
Anna
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deFazio
David D L
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Bowtell
D000368:Aged; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D002879:Chromosomes, Human, Pair 10; D002889:Chromosomes, Human, Pair 2; D041321:Chromosomes, Human, X; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008875:Middle Aged; D060787:Neoplasm Grading; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D011973:Receptors, LDL / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*
D004273:DNA, Neoplasm; C434476:LRP1B protein, human; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D004317:Doxorubicin