FIGURE 7.

Statins induce two independent responses in multiple myeloma. As observed in AML, DLBCL, and now multiple myeloma, statins upregulate PUMA in a p53-independent manner. PUMA can contribute to BH3 mimetic killing by promiscuously binding prosurvival BCL2 family members. Activation of the integrated stress response is a multiple myeloma–specific statin response that influences apoptosis. Through a currently undefined mechanism, statins reduced general translation and activate the translation of ATF4. ATF4 is a master mediator of the ISR. One such output of ATF4 is upregulation of NOXA. NOXA can be partially reduced with ISRIB which results in the partial rescue from statin-mediated apoptotic sensitization to venetoclax. The MCL-1 selective activity of NOXA promotes sensitivity to venetoclax. However, this property also makes it a direct competitor with S63845. As such, ISRIB did not rescue from S63845 and statin-mediated killing.