NOXA genetic amplification or pharmacologic induction primes lymphoma cells to BCL2 inhibitor-induced cell death

Yuxuan Liu; Patrizia Mondello; Tatiana Erazo; Neeta Bala Tannan; Zahra Asgari; Elisa de Stanchina; Gouri Nanjangud; Venkatraman E. Seshan; Shenqiu Wang; Hans-Guido Wendel; Anas Younes

doi:10.1073/pnas.1806928115

New Research In

Edited by T. W. Mak, The Campbell Family Institute for Breast Cancer Research at the Princess Margaret Cancer Centre, Toronto, ON, Canada, and approved October 12, 2018 (received for review April 22, 2018)

Significance

BCL2 selective inhibitors are promising agents currently under clinical investigation for treatment of BCL2-dependent cancers. However, the clinical activity of BCL2 inhibitors in patients with diffuse large B cell lymphoma (DLBCL) has been disappointing. In this study, we identified PMAIP1/NOXA gene amplification as a marker of sensitivity to BCL2 inhibitors in DLBCL. Cells lacking NOXA amplification were less sensitive to BCL2 inhibitors due to codependency on MCL1 and BCL2 proteins. We show that pharmacologic induction of NOXA by the HDAC inhibitor panobinostat primes DLBCL to BCL2 inhibitor-induced cell death by disrupting the codependency on BCL2 and MCL1, mimicking the biologic effects of NOXA genetic amplification. Our data provide a mechanistic rationale for combining HDAC inhibitors with BCL2 inhibitors in DLBCL.

Abstract

Although diffuse large B cell lymphoma (DLBCL) cells widely express the BCL2 protein, they rarely respond to treatment with BCL2-selective inhibitors. Here we show that DLBCL cells harboring PMAIP1/NOXA gene amplification were highly sensitive to BCL2 small-molecule inhibitors. In these cells, BCL2 inhibition induced cell death by activating caspase 9, which was further amplified by caspase-dependent cleavage and depletion of MCL1. In DLBCL cells lacking NOXA amplification, BCL2 inhibition was associated with an increase in MCL1 protein abundance in a BIM-dependent manner, causing a decreased antilymphoma efficacy. In these cells, dual inhibition of MCL1 and BCL2 was required for enhanced killing. Pharmacologic induction of NOXA, using the histone deacetylase inhibitor panobinostat, decreased MCL1 protein abundance and increased lymphoma cell vulnerability to BCL2 inhibitors in vitro and in vivo. Our data provide a mechanistic rationale for combination strategies to disrupt lymphoma cell codependency on BCL2 and MCL1 proteins in DLBCL.

Footnotes

↵¹Y.L. and P.M. contributed equally to this work.
↵²To whom correspondence should be addressed. Email: younesa{at}mskcc.org.

Author contributions: Y.L., P.M., T.E., N.B.T., E.d.S., G.N., S.W., H.-G.W., and A.Y. designed research; Y.L., P.M., T.E., N.B.T., Z.A., E.d.S., and G.N. performed research; S.W. and H.-G.W. contributed new reagents/analytic tools; Y.L., P.M., T.E., N.B.T., Z.A., E.d.S., G.N., V.E.S., H.-G.W., and A.Y. analyzed data; and Y.L., P.M., T.E., N.B.T., H.-G.W., and A.Y. wrote the paper.
Conflict of interest statement: A.Y. has potential conflicts of interest; funds for research came from Servier and for clinical trials from Servier and Novartis.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1806928115/-/DCSupplemental.

This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

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