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Clin Lymphoma Myeloma Leuk. 2019 Jul;19(7):397-405. doi: 10.1016/j.clml.2019.03.017. Epub 2019 Mar 25.

Future of Personalized Therapy Targeting Aberrant Signaling Pathways in Multiple Myeloma.

Author information

1
Taussig Cancer Center, Department of Hematology, Medical Oncology, Cleveland Clinic, Cleveland, OH. Electronic address: anwerf@ccf.org.
2
Department of Molecular and Cellular Biology, The University of Arizona, Tucson, AZ.
3
Department of Medicine, The University of Arizona, Tucson, AZ.
4
Department of Medicine, Summit Medical Group, Summit, NJ.
5
College of Public Health, The University of Arizona, Tucson, AZ.
6
Department of Medicine, Division of Hematology & Oncology, The University of Arizona, Tucson, AZ.
7
Division of Human Genetics, Children's Hospital, Cincinnati, OH.
8
College of Pharmacy, The University of Arizona, Tucson, AZ.
9
Taussig Cancer Center, Department of Hematology, Medical Oncology, Cleveland Clinic, Cleveland, OH.

Abstract

Multiple myeloma (MM) is a genetically complex disease. Identification of mutations and aberrant signaling pathways that contribute to the progression of MM and drug resistance has potential to lead to specific targets and personalized treatment. Aberrant signal pathways include RAS pathway activation due to RAS or BRAF mutations (targeted by vemurafenib alone or combined with cobimetinib), BCL-2 overexpression in t(11:14) (targeted by venetoclax), JAK2 pathway activation (targeted by ruxolitinib), NF-κB pathway activation (treated with DANFIN combined with bortezomib), MDM2 overexpression, and PI3K/mTOR pathway activation (targeted by BEZ235). Cyclin D1 (CCND1) and MYC are also emerging as key potential targets. In addition, histone deacetylase inhibitors are already in use for the treatment of MM in combination therapy, and targeted inhibition of FGFR3 (AZD4547) is effective in myeloma cells with t(4;14) translocation. Bromodomain and extra terminal (BET) protein antagonists decrease the expression of MYC and have displayed promising antimyeloma activity. A better understanding of the alterations in signaling pathways that promote MM progression will further inform the development of precision therapy for patients.

KEYWORDS:

Intracellular pathway; MM; Mutations; Precision medicine; Targeted therapy

PMID:
31036508
PMCID:
PMC6626550
[Available on 2020-07-01]
DOI:
10.1016/j.clml.2019.03.017

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