Novel inhibitors are cytotoxic for myeloma cells with NFkB inducing kinase-dependent activation of NFkB

Abstract

// Yulia N. Demchenko 1 , Leslie A. Brents 1 , Zhihong Li 2 , Leif P. Bergsagel 3 , Lawrence R. McGee 2 , and Michael W. Kuehl 1 1 Genetics Branch, National Cancer Institute, Bethesda, MD, USA 2 Amgen, Inc. South San Francisco CA, USA 3 Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale Correspondence: Michael Kuehl, email: // Keywords : NFkB-inducing kinase, NIK inhibitors, NFkB, IKKbeta inhibitors, multiple myeloma. Received : May 20, 2014 Accepted : June 21, 2014 Published : June 23, 2014 Abstract NFkB activity is critical for survival and proliferation of normal lymphoid cells and many kinds of B-cell tumors, including multiple myeloma (MM). NFkB activating mutations, which are apparent progression events, enable MM tumors to become less dependent on bone marrow signals that activate NFkB. Mutations that activate NFkB-inducing kinase (NIK) protein are the most prevalent among the many kinds of NFkB mutations in MM tumors. NIK is the main activating kinase of the alternative NFkB pathway, although over-expression of NIK also can activate the classical pathway. Two NIK inhibitors and an isomeric control were tested with human myeloma cell lines. These specific NIK inhibitors are selectively cytotoxic for cells with NIK-dependent activation of NFkB. Combination therapy targeting NIK and IKKbeta (as a main kinase of the classical NFkB pathway) represents a promising treatment strategy in MM. NIK inhibitors can also be useful tool for assessing the role of NIK and alternative NFkB pathway in different cells.