Oncotarget

Research Papers:

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. Lin and Dipen Maru _

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Oncotarget. 2019; 10:4703-4718. https://doi.org/10.18632/oncotarget.27095

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Abstract

Omkara Lakshmi Veeranki1, Zhimin Tong1, Rashmi Dokey1, Alicia Mejia1, Jianhu Zhang2, Yawei Qiao2, Pankaj Kumar Singh2, Riham Katkhuda3, Barbara Mino3, Ramesh Tailor4, Jaime Rodriguez Canales3, Roland Bassett5, Jaffer Ajani6, Ji Yuan Wu6, Scott Kopetz6, Mariela Blum6, Wayne Hofstetter7, Michael Tetzlaff1, Sunil Krishnan8, Steven H. Lin8 and Dipen Maru1,3

1 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2 Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3 Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4 Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

5 Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

6 Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

7 Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

8 Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence to:

Dipen Maru,email: dmaru@mdanderson.org

Keywords: CDK 9 Inhibitor; esophageal adenocarcinoma; radiation; Axl

Received: March 01, 2019     Accepted: July 01, 2019     Published: July 23, 2019

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.


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