Targeting cyclin-dependent kinase 9 by a novel inhibitor enhances radiosensitization and identifies Axl as a novel downstream target in esophageal adenocarcinoma

Omkara Lakshmi Veeranki, Zhimin Tong, Rashmi Dokey, Alicia Mejia, Jianhu Zhang, Yawei Qiao, Pankaj Kumar Singh, Riham Katkhuda, Barbara Mino, Ramesh Tailor, Jaime Rodriguez Canales, Roland Bassett, Jaffer Ajani, Ji Yuan Wu, Scott Kopetz, Mariela Blum, Wayne Hofstetter, Michael Tetzlaff, Sunil Krishnan, Steven H. LinDipen Maru

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Cyclin-dependent kinase 9 (CDK9) transcriptionally regulates several proteins and cellular pathways central to radiation induced tissue injury. We investigated a role of BAY1143572, a new highly specific CDK9 inhibitor, as a sensitizer to radiation in esophageal adenocarcinoma. In vitro synergy between the CDK9 inhibitor and radiation was evaluated by clonogenic assay. In vivo synergy between the CDK9 inhibitor and radiation was assessed in multiple xenograft models including a patient's tumor derived xenograft (PDX). Reverse phase protein array (RPPA), western blotting, immunohistochemistry, and qPCR were utilized to identify and validate targets of the CDK9 inhibitor. The CDK9 inhibitor plus radiation significantly reduced growth of FLO-1, SKGT4, OE33, and radiation resistant OE33R xenografts and PDXs as compared to the cohorts treated with either single agent CDK9 inhibitor or radiation alone. RPPA identified Axl as a candidate target of CDK9 inhibition. Western blot and qPCR demonstrated reduced Axl mRNA (p = 0.02) and protein levels after treatment with CDK9 inhibitor with or without radiation in FLO-1 and SKGT4 cells. Axl protein expression in FLO-1 xenografts treated with combination of CDK9 inhibitor and radiation was significantly lower than the xenografts treated with radiation alone (p = 0.003). Clonogenic assay performed after overexpression of Axl in FLO-1 and SKGT4 cells enhanced radiosensitization by the CDK9 inhibitor, suggesting dependency of radiosensitization effects of the CDK9 inhibitor on Axl. In conclusion, these findings indicate that targeting CDK9 by BAY1143572 significantly enhances the effects of radiation and Axl is a novel downstream target of CDK9 in esophageal adenocarcinoma.

Original languageEnglish (US)
Pages (from-to)4703-4718
Number of pages16
JournalOncotarget
Volume10
Issue number45
DOIs
StatePublished - 2019

Keywords

  • Axl
  • CDK 9 Inhibitor
  • Esophageal adenocarcinoma
  • Radiation

ASJC Scopus subject areas

  • Oncology

MD Anderson CCSG core facilities

  • Flow Cytometry and Cellular Imaging Facility
  • Functional Proteomics Reverse Phase Protein Array Core
  • Bioinformatics Shared Resource
  • Research Animal Support Facility
  • Advanced Technology Genomics Core
  • Cytogenetics and Cell Authentication Core

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