Targeting anti-apoptotic proteins in multiple myeloma
Centro de Investigación del Cáncer (CIC-IBMCC)
Multiple myeloma (MM) is a hematological malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). The use of new targeted drugs together with immunotherapeutic approaches has notably prolonged the survival of patients with MM. However, MM remains an incurable disease, and preclinical studies of drugs with different mechanisms of action are needed.
Apoptosis evasion has been postulated as one of the main mechanisms by which tumor cells could survive after therapy. We will present preclinical evaluation studies of the single and dual inhibition of MCL-1 and BCL-2 anti-apoptotic proteins with BH3 mimetic agents S63845 and venetoclax. We first confirmed the anti-tumor activity of venetoclax and S63845 as single agents on myeloma cell lines. S63845 and venetoclax remained active in the presence of mesenchymal stromal cells from MM patients (pMSCs), being the inhibition of MCL-1, contrary to the inhibition of BCL-2, more effective under these conditions. A mechanism based on the modulation of MCL-1 and BCL-2 expression by microRNAs 193-3p and mir-21-5p was discovered. We also observed that, both in monoculture and co-culture conditions, these drugs prevented the interaction of their respective target proteins with the pro-apoptotic protein BIM. However, concomitant interaction of the non-targeted anti-apoptotic proteins with BIM was evidenced, thus revealing a shift of dependency as a potential resistance mechanism. To overcome this mechanism of resistance, the combination of S63845 + venetoclax was evaluated in in vitro, in vivo, and ex vivo assays. The favorable preclinical results obtained supported the future clinical development of the S63845 and venetoclax combination for the treatment of MM patients.
Finally, we searched for genes that could modulate the response to S63845 or venetoclax in MM cells through genome-wide CRISPR activation screening. As expected, the overexpression of several genes coding for anti-apoptotic proteins other than the targeted protein conferred resistance, while the activation of the transcription of different genes coding for pro-apoptotic proteins sensitized tumor cells to these agents. Besides, the overexpression of other genes related to the pathophysiology of the disease were relevant for the response to S63845 or venetoclax and are currently under study.