David Segal, and Yuan Yao
Photo from the Walter
and Eliza Hall Institute
A new class of inhibitors may be effective in treating a majority of patients with multiple myeloma (MM), according to research published in Blood.
Experiments in multiple MM cell lines suggested the majority of myelomas rely on the protein MCL1 to stay alive.
And targeting MCL1 inhibited disease progression in mouse models of MM.
Therefore, researchers believe drugs designed to inhibit MCL1 may be a promising treatment option for MM.
“Our research shows that switching off MCL1 has the potential to be an effective new treatment approach for the majority of patients with myeloma,” said Jianan Gong, PhD, of The Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
For this study, Dr Gong and her colleagues investigated the survival proteins that keep MM cells alive.
The team found that a majority of MM cell lines—about 70%—died when MCL1 was switched off. This included well-established, immortalized MM cell lines (17/25) and low-passage MM cell lines (5/7).
“In contrast, only around one quarter [of the cell lines] were susceptible to inhibiting BCL2,” Dr Gong said. “This finding is in keeping with earlier research at the Walter and Eliza Hall Institute that pinpointed MCL1 as the likely protein that keeps myeloma cells alive.”
The researchers also found that targeting MCL1 hindered MM growth in vivo.
The team targeted MCL1 by expressing the MCL1-selective ligand BIM2A in mice inoculated with 1 of 2 MM cell lines—AMO1 and H929. In both models, targeting MCL1 resulted in delayed disease progression and reduced disease burden.
Finally, the researchers identified a subtype of MM that is highly dependent upon BCLXL, so they’ve theorized that targeting both MCL1 and BCLXL could prove useful.
The team concluded that MCL1 is pivotal for maintaining the survival of most myelomas, so targeting the protein should be prioritized once validated inhibitors become available.
“As yet, these inhibitors are still in preclinical development,” said study author Andrew Roberts, MBBS, PhD, of The Walter and Eliza Hall Institute of Medical Research.
“Our results suggest that, once necessary laboratory testing for safety is completed, clinical trials of their effectiveness in treating patients with multiple myeloma that is no longer responding to current therapies would be well justified.”
