Potential Biomarker for Carfilzomib Activity in CLL

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Carfilzomib (Kyprolis) is active in B-cell neoplasms but exhibits heterogeneous activity in chronic lymphocytic leukemia (CLL) samples. As reported in Clinical Cancer Research, Lamothe and colleagues examined the mechanism by which carfilzomib induces CLL cell death.

In studies using CLL patient samples and cell lines, complementary knockdown and knockout cells, and carfilzomib-resistant cell lines, changes in intracellular networks were investigated to identify molecules responsible for cytotoxic activity. It was found that carfilzomib induced endoplasmic reticulum stress and activation of both intrinsic and extrinsic apoptotic pathways via alteration of the ubiquitin proteasome pathway. The transcription factor CHOP (CCAAT/enhancer-binding protein homology protein) accumulated in response to carfilzomib exposure, with CHOP depletion conferring protection against cytotoxicity. Carfilzomib also induced accumulation of MCL-1 and Noxa, with MCL-1 preferentially forming a complex with Noxa and interfering with the protective effect of MCL-1 in sequestering Bak. Depletion of Noxa or both Bak and Bax conferred protection against carfilzomib-induced cell death.

The investigators concluded: “Collectively, carfilzomib induced [endoplasmic reticulum] stress, culminating in activation of intrinsic and extrinsic caspase pathways, and we identified the CHOP protein level as a biomarker that could predict sensitivity to carfilzomib in CLL.”

Lamothe B, et al: Clin Cancer Res. March 29, 2016 (early release online).




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