The Covalent CDK7 Inhibitor THZ1 Potently Induces Apoptosis in Multiple Myeloma Cells In Vitro and In Vivo.

ABSTRACT:

Purpose

The goal of this study was to characterize the activity of the covalent CDK7 inhibitor THZ1 in multiple myeloma models.

Experimental design

Multiple myeloma lines were exposed to varying THZ1 concentrations alone or with carfilzomib or ABT-199, after which apoptosis was monitored by flow cytometry, protein expression by Western blot analysis, mRNA by RT-PCR. Analogous studies were performed in cells ectopically expressing c-MYC, MCL-1, or BCL-XL, or CRISPER-Cas CDK7 sgRNA knockout. Primary multiple myeloma cells were exposed to THZ1 ± carfilzomib or ABT-199. In vivo effects of THZ1 were examined in a systemic U266 xenograft model.

Results

THZ1 markedly diminished multiple myeloma cell proliferation and survival despite bortezomib or stromal cell resista

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC6801078 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature