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Waldenstrom macroglobulinemia cells devoid of BTK^C481S or CXCR4^WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment.

ABSTRACT: Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9-3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTK^C481S and CXCR4^WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-speci

SUBMITTER: Paulus A

PROVIDER: S-EPMC5518884 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Dataset Information

Waldenstrom macroglobulinemia cells devoid of BTK^C481S or CXCR4^WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment.

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment.

OmicsDI is part of the ELIXIR infrastructure

Tweets

Waldenstrom macroglobulinemia cells devoid of BTK^C481S or CXCR4^WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment.