Multiple myeloma is a genomic and phenotypic heterogeneous disease, and thus challenging to treat. Discoveries of non-oncogenic addiction factors, that is, genes that are not affected by mutations and required for all myelomas to survive, would be highly beneficial for identifying new therapeutical targets.

Using an unbiased RNA interference screen, Staudt and colleagues (Cancer Cell http://doi.org/k69; 2013) identified caspase-10 as a non-oncogenic addiction target in myeloma, but not in lymphoma, lines. Myeloma viability was found to be dependent on catalytically active caspase-10. The master transcription factor IRF4, which is essential for survival of myeloma, was shown to upregulate both capase-10 and the large isoform of caspase-like protein (cFLIPL) in myeloma cells; furthermore, cFLIPL interacted with caspase-10 to increase its activity. Interestingly, inhibition of caspase-10 did not affect apoptosis, but instead increased autophagic flux. BCL-2-associated transcription factor 1 (BCLAF1), which is known to be toxic when over-expressed, was identified as a proteolytic target of caspase-10. The authors found that BCLAF1, which binds BCL-2, accumulates following caspase-10 inhibition, leading to autophagy induction due to the displacement of the autophagy-inducing protein beclin-1 from BCL-2.

This study shows that caspase-10 is required to maintain a basal level of autophagy essential for myeloma survival, whereas inhibition of caspase-10 induces autophagic cell death, which could be exploited therapeutically.