2. Academic Validation
  3. Bromodomain inhibitor treatment leads to overexpression of multiple kinases in cancer cells

Bromodomain inhibitor treatment leads to overexpression of multiple kinases in cancer cells

  • Neoplasia. 2024 Nov:57:101046. doi: 10.1016/j.neo.2024.101046.
Darshan S Chandrashekar 1,  Farrukh Afaq 2,  Santhosh Kumar Karthikeyan 2,  Mohammad Athar 3,  Sadeep Shrestha 4,  Rajesh Singh 5,  Upender Manne 6,  Sooryanarayana Varambally 7
Affiliations

Affiliations

  • 1 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: [email protected].
  • 2 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 3 Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 4 Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
  • 5 Morehouse School of Medicine, Atlanta, GA, USA.
  • 6 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 7 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Biomedical Informatics and Data Science, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: [email protected].
PMID: 39241280 DOI: 10.1016/j.neo.2024.101046
Abstract

The bromodomain and extraterminal (BET) family of proteins show altered expression across various cancers. The members of the bromodomain (BRD) family contain epigenetic reader domains that bind to acetylated lysine residues in both histone and non-histone proteins. Since BRD proteins are involved in Cancer initiation and progression, therapeutic targeting of these proteins has recently been an area of interest. In experimental settings, JQ1, a commonly used Brd Inhibitor, is the first known inhibitor to target BRD-containing protein 4 (BRD4), a ubiquitously expressed BRD and extraterminal family protein. BRD4 is necessary for a normal cell cycle, and its aberrant expression activates pro-inflammatory cytokines, leading to tumor initiation and progression. Various BRD4 inhibitors have been developed recently and tested in preclinical settings and are now in clinical trials. However, as with many targeted therapies, Brd Inhibitor treatment can lead to resistance to treatment. Here, we investigated the kinases up-regulated on JQ1 treatment that may serve as target for combination therapy along with BRD inhibitors. To identify kinase targets, we performed a comparative analysis of gene expression data using RNA from BRD inhibitor-treated cells or BRD-modulated cells and identified overexpression of several kinases, including Fyn, NEK9, and ADCK5. We further validated, by immunoblotting, the overexpression of Fyn tyrosine kinase; NEK9 serine/threonine kinase and ADCK5, an atypical kinase, to confirm their overexpression after Brd Inhibitor treatment. Importantly, our studies show that targeting Fyn or NEK9 along with Brd Inhibitor effectively reduces proliferation of Cancer cells. Therefore, our research emphasizes a potential approach of utilizing inhibitors targeting some of the overexpressed kinases in conjunction with BRD inhibitors to enhance therapeutic effectiveness.

Keywords

Cancer; Gene Expression; Kinases; Resistance.

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