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Cancer Res. 2015 May 15;75(10):2071-82. doi: 10.1158/0008-5472.CAN-14-3400. Epub 2015 Mar 13.

Metabolic signature identifies novel targets for drug resistance in multiple myeloma.

Author information

1
Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
2
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
3
Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. irene_ghobrial@dfci.harvard.edu.

Abstract

Drug resistance remains a major clinical challenge for cancer treatment. Multiple myeloma is an incurable plasma cell cancer selectively localized in the bone marrow. The main cause of resistance in myeloma is the minimal residual disease cells that are resistant to the original therapy, including bortezomib treatment and high-dose melphalan in stem cell transplant. In this study, we demonstrate that altered tumor cell metabolism is essential for the regulation of drug resistance in multiple myeloma cells. We show the unprecedented role of the metabolic phenotype in inducing drug resistance through LDHA and HIF1A in multiple myeloma, and that specific inhibition of LDHA and HIF1A can restore sensitivity to therapeutic agents such as bortezomib and can also inhibit tumor growth induced by altered metabolism. Knockdown of LDHA can restore sensitivity of bortezomib resistance cell lines while gain-of-function studies using LDHA or HIF1A induced resistance in bortezomib-sensitive cell lines. Taken together, these data suggest that HIF1A and LDHA are important targets for hypoxia-driven drug resistance. Novel drugs that regulate metabolic pathways in multiple myeloma, specifically targeting LDHA, can be beneficial to inhibit tumor growth and overcome drug resistance.

PMID:
25769724
PMCID:
PMC4433568
DOI:
10.1158/0008-5472.CAN-14-3400
[Indexed for MEDLINE]
Free PMC Article

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