Journal
BLOOD
Volume 115, Issue 23, Pages 4787-4797Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-07-230508
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Funding
- Canada Research Chairs Program
- Ontario Institute for Cancer Research, Province of Ontario
- Canadian Institutes for Health Research
- Natural Sciences and Engineering Research Council
- Leukemia & Lymphoma Society of Canada
- Ontario Graduate Scholarship
- Multiple Myeloma Research Foundation
- Ontario Ministry of Health and Long Term Care
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Statin inhibitors, used to control hypercholesterolemia, trigger apoptosis of hematologic tumor cells and therefore have immediate potential as anticancer agents. Evaluations of statins in acute myelogenous leukemia and multiple myeloma have shown that statin efficacy is mixed, with only a subset of tumor cells being highly responsive. Our goal was to distinguish molecular features of statin-sensitive and -insensitive myeloma cells and gain insight into potential predictive markers. We show that dysregulation of the mevalonate pathway is a key determinant of sensitivity to statin-induced apoptosis in multiple myeloma. In sensitive cells, the classic feedback response to statin exposure is lost. This results in deficient up-regulation of 2 isoforms of hydroxymethylglutaryl coenzyme A reductase: the rate-limiting enzyme of the mevalonate pathway and hydroxymethylglutaryl coenzyme A synthase 1. To ascertain the clinical utility of these findings, we demonstrate that a subset of primary myeloma cells is sensitive to statins and that monitoring dysregulation of the mevalonate pathway may distinguish these cancers. We also show statins are highly effective and well tolerated in an orthotopic model of myeloma using cells harboring this dysregulation. This determinant of sensitivity further provides molecular rationale for the significant therapeutic index of statins on these tumor cells. (Blood. 2010;115(23):4787-4797)
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