Authors
Susu Zhang, Kathleen L Engel, Assil Fahs, Ara Jo, Clare F Malone, Kenneth N Ross, Marissa Just, Brian Guedes, Diyana Granum, Kristianne M Oristian, Alexander R Kovach, Gabriela Alexe, Giulia DiGiovanni, Leen Barbar, Rex C Bentley, Christian G Cerda-Smith, Ozgun Le Roux, Elizabeth A Mendes, Seth Parker Zimmerman, Audrey Taillon, Vivian Tong, Allen Basanthakumar, Matthew G Rees, Jennifer A Roth, Jack F Shern, Kris C Wood, Christopher M Counter, Corinne M Linardic, Kimberly Stegmaier
Published in
Cancer discovery. Jul 14, 2026. Epub Jul 14, 2026.
Abstract
Alveolar rhabdomyosarcoma (aRMS) is a fusion-driven pediatric cancer with poor survival and limited therapeutic options. To uncover novel vulnerabilities, we employed complex-based analysis of the DepMap functional genomic data, identifying CDK8 as a dependency in aRMS. Both CDK8 knockout and pharmacologic inhibition impaired tumor cell growth and induced myogenic differentiation in vitro and in vivo. Compared to genetic loss, CDK8 pharmacologic inhibition induced more dynamic transcriptional changes. With a genome-scale CRISPR-Cas9 drug modifier screen, we determined that the maximal anti-tumor activity of the CDK8 inhibitor requires the presence of the Mediator kinase module, including CDK8, and transcriptional cooperation with the SAGA complex. We further identified SIX4 as a key transcription factor mediating CDK8 inhibitor-induced transcriptional activation of myogenic differentiation genes and impaired tumor proliferation. These findings suggest a distinct gain-of-function mechanism of the CDK8 inhibitor and establish a strong rationale for CDK8 inhibition as a differentiation-inducing therapeutic strategy in aRMS.
PMID:
42447071
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.
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