Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199).

E Litvinovich,Y Xiao,D C Phillips,L T Lam,L Roberts-Rapp,J D Leverson,A J Souers

doi:10.1038/bcj.2015.88

E Litvinovich, Y Xiao + Show 5 more

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https://doi.org/10.1038/bcj.2015.88

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Abstract

As a population, non-Hodgkin's lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2High) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2High cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-XL-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2High NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2Low NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-XL inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2Low) that could benefit from BCL-XL (navitoclax)-driven combination therapy.

Highlights

Apoptosis or programmed cell death is an evolutionarily conserved cellular process that is required for normal embryonic development and maintenance of tissue homeostasis
Segregation of non-Hodgkin’s lymphoma (NHL) cell lines into BCL2High (t(14;18)+ and/or high BCL2 copy number (CN)) and BCL2Low groups identifies the former group as being sensitive to venetoclax.[20]
To assess the contribution of BCL-XL for survival, we treated all NHL cell lines with BCL-XL-selective inhibitor A-1155463.31 As expected, BCL2High cell lines were resistant to the BCL-XL-selective inhibitor A-1155463 (EC50 45 μM)

Summary

Introduction

Apoptosis or programmed cell death is an evolutionarily conserved cellular process that is required for normal embryonic development and maintenance of tissue homeostasis. The B-cell lymphoma protein-2 (BCL-2) family of proteins are essential regulators of apoptosis, functioning as either activators or inhibitors of cell death primarily at the mitochondrial level. This family of proteins consists of three groups that each contain at least one BCL-2 homology (BH) motif (BH1-4). The pro-apoptotic ‘BH3-only’ proteins, BID, BIM, PUMA, NOXA, BAD, BIK, BMF and HRK are activated or induced by cell death stimuli that, in turn, may activate the pro-apoptotic ‘multidomain effector’ proteins BAX and BAK. Once activated, these proteins homo-oligomerize to induce mitochondrial outer membrane permeabilization. Aberrant expression and/or function of BCL-2 family members results in deregulation of apoptosis that contributes to the development of a variety of human pathologies including cancer, neurodegeneration and autoimmunity.[1,2]

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