Advertisement

Hierarchy for targeting pro-survival BCL2 family proteins in multiple myeloma: pivotal role of MCL1

Jia-Nan Gong, Tiffany Khong, David Segal, Yuan Yao, Chris D. Riffkin, Jean-Marc Garnier, Seong Lin Khaw, Guillaume Lessene, Andrew Spencer, Marco J. Herold, Andrew W. Roberts and David C.S. Huang

Key points

  • Only a minority of myeloma cell lines are killed when the pro-survival BCL2 or BCLXL are selectively inhibited with BH3 mimetic compounds.

  • In contrast, targeting MCL1 readily killed ~70% of the myeloma cell lines tested including both low-passage and well-established ones.

Abstract

New therapeutic targets are needed to address the poor prognosis of patients with high-risk multiple myeloma. Myeloma cells usually express a range of the pro-survival BCL2 proteins. To define the hierarchy of their relative importance for maintaining the survival of myeloma cells, we targeted each of them in a large panel of cell lines using pharmacological inhibitors, gene editing or by peptide-based approaches, alone or in combination. The majority of well-established immortalized cell lines (17/25) or low-passage myeloma cell lines (5/7) are readily killed when MCL1 is targeted, even including those cell lines sensitive to BCL2 inhibition. Targeting MCL1 also constrained the growth of myeloma in vivo. We also identified a previously unrecognized sub-set of myeloma that is highly BCLXL-dependent, and the potential for co-targeting MCL1 and BCLXL. As MCL1 is pivotal for maintaining survival of most myelomas, it should be prioritized for targeting in the clinic once high quality, validated inhibitors become available.

  • Submitted March 10, 2016.
  • Accepted July 13, 2016.