PLX150436

GSE79955: CDK7 targeting in peripheral T-cell lymphomas abrogates STAT activity causing apoptosis and sensitization to BCL2 inhibitors

• Organsim human
• Type RNASEQ
• Target gene
• Project ARCHS4

Peripheral T-cell lymphomas (PTCL) are clinically aggressive diseases with poor response to available chemotherapy regimens and dismal survival. To identify active drugs and therapeutic targets for PTCL patients, we performed a cell-based progressive screen from a library of 101 anti-neoplastic compounds with known targets that are in clinical stage. We identified three therapeutic targets across a panel of PTCL cell lines: lysine deacetylases, proteasome and RNA polymerase II. In this latter group, the covalent inhibitor of cyclin-dependent kinase 7 (CDK7), THZ1, demonstrated high potency and activity in PTCL-NOS and ALCL-ALKneg cells. To determine the mechanism of CDK7 inhibition, we conducted RNA-seq in OCI-Ly13.2 cells treated with THZ1 500 nM (or vehicle). We found that the STAT-signaling pathway is highly vulnerable to CDK7 inhibition. THZ1 abrogated STAT signaling even in cell lines with an activating STAT3 mutation. Moreover, CDK7 inhibition decreases the expression of highly transcribed genes like MYC contributing to the anti-lymphoma effect of THZ1. In surviving cells, THZ1 decreased the expression of the anti-apoptotic BH3 family member MCL1 making cells reliant on BCL2 and BCL-XL for survival, and thus more susceptible to BH3 mimetic drugs. Accordingly, sequential combination of THZ1 and obatoclax yielded a higher lymphoma growth control in a human PTCL-NOS xenograft model harboring a STAT3 mutation, delineating a molecularly tailored therapy for PTCL patients. SOURCE: Tharu,M,Fernando (tmf2001@med.cornell.edu) - Ari Melnick Weill Cornell Medical College