Multiple myeloma is a clonal B-cell malignancy characterized by complex genetic aberrations. In spite of recent improvements, this disease remains incurable and treatment options for relapse/refractory disease are limited. A promising class of novel agents to treat patients with other B-cell malignancies is the BH3 mimetic compounds to target the pro-survival Bcl-2 proteins. For example, the majority of patients with CLL (chronic lymphocytic leukaemia) respond to venetoclax (ABT-199), a Bcl-2-selective inhibitor. Some myeloma cell lines are also sensitive to Bcl-2 inhibition but it is not entirely clear which of the other Bcl-2-related proteins (Bcl‑xL, Bcl‑w, Mcl‑1 or Bfl‑1) play a role.
To determine this, we screened a large panel (20) of myeloma cell lines to killing by BH3 mimetics with varying specificities, or genetic approaches to target Bcl‑2 or its relatives. In accord with published data, we found that 3 cell lines are very sensitive to Bcl-2 inhibition and 4 to Bcl-xL inhibition. These results suggest that other pro-survival proteins play a role or that targeting more than one of them is required for efficient cell killing. To address this, we targeted them genetically using CRISPR/Cas9 technology. Efficient deletion of these genes was achieved and strikingly (NN/20 cell lines) died rapidly in the absence of Mcl-1. Thus, most myeloma cell lines rely on Mcl-1. To confirm this, we used a Mcl-1-selective peptidyl antagonist and found that cells sensitive to Mcl-1 deletion were also readily killed by a Mcl‑1 antagonist. Encouragingly, we observed that such tumours rapidly responded to this antagonist in vivo.
Taken together, these studies identify Mcl-1 as the key survival factor for most myeloma cell lines. The goal of our ongoing studies is to establish if this holds for primary patient samples as selective Mcl-1 inhibition may be a promising approach for treating multiple myeloma.