Oncotarget

Research Papers:

Therapeutic inhibition of Mcl-1 blocks cell survival in estrogen receptor-positive breast cancers

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Oncotarget. 2019; 10:5389-5402. https://doi.org/10.18632/oncotarget.27070

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Michelle M. Williams, David L. Elion, Bushra Rahman, Donna J. Hicks, Violeta Sanchez and Rebecca S. Cook

Abstract

Michelle M. Williams1, David L. Elion1, Bushra Rahman2, Donna J. Hicks2, Violeta Sanchez3 and Rebecca S. Cook1,2,4,5

1 Program in Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA

2 Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA

3 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA

4 Department of Biomedical Engineering, Vanderbilt University, Nashville TN 37232, USA

5 The Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA

Correspondence to:

Rebecca S. Cook,email: Rebecca.cook@vanderbilt.edu

Keywords: Mcl-1; ABT-263 resistance; mTORC1 signaling; luminal breast cancers

Received: April 23, 2019     Accepted: June 14, 2019     Published: September 10, 2019

ABSTRACT

Cancers often overexpress anti-apoptotic Bcl-2 proteins for cell death evasion, a recognized hallmark of cancer progression. While estrogen receptor (ER)-α+ breast cancers express high levels of three anti-apoptotic Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1), pharmacological inhibition of Bcl-2 and/or Bcl-xL fails to induce cell death in ERα+ breast cancer cell lines, due to rapid and robust Mcl-1 upregulation. The mechanisms of acute Mcl-1 upregulation in response to Bcl-2/Bcl-xL inhibition remain undefined in in ERα+ breast cancers. We report here that blockade of Bcl-2 or Bcl-xL, alone or together, rapidly induced mTOR signaling in ERα+ breast cancer cells, rapidly increasing cap-dependent Mcl-1 translation. Cells treated with a pharmacological inhibitor of cap-dependent translation, or with the mTORC1 inhibitor RAD001/everolimus, displayed reduced protein levels of Mcl-1 under basal conditions, and failed to upregulate Mcl-1 protein expression following treatment with ABT-263, a pharmacological inhibitor of Bcl-2 and Bcl-xL. Although treatment with ABT-263 alone did not sustain apoptosis in tumor cells in culture or in vivo, ABT-263 plus RAD001 increased apoptosis to a greater extent than either agent used alone. Similarly, combined use of the selective Mcl-1 inhibitor VU661013 with ABT-263 resulted in tumor cell apoptosis and diminished tumor growth in vivo. These findings suggest that rapid Mcl-1 translation drives ABT-263 resistance, but can be combated directly using emerging Mcl-1 inhibitors, or indirectly through existing and approved mTOR inhibitors.



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