Efficacy of the HSP70 inhibitor PET-16 in multiple myeloma

Multiple myeloma (MM) is a common and largely incurable blood Cancer for which new treatment options are needed, as resistance to current modalities is an issue. Additionally, because this tumor type often resides in a hypoxic niche of the bone marrow, new therapeutics that remain effective even under hypoxic conditions are sought. Because of the secretory nature of MM cells they are uniquely under proteotoxic stress, and we hypothesized that these tumor cells may alleviate this stress by upregulating the major stress-induced cytosolic form of the chaperone HSP70. In this work we test the efficacy of the HSP70 Inhibitor PET-16 for MM. We show that MM cell lines express significant levels of HSP70, and further that inhibition of HSP70 causes decreased viability and Apoptosis, along with proteotoxic stress, as assessed by the accumulation of poly-ubiquitylated proteins. Importantly, we show that growth of these tumor cells under hypoxic conditions has no effect on the ability of PET-16 to be cytotoxic. The HSP70 Inhibitor PET-16 should thus be considered further for pre-clinical analyses of efficacy in MM.

HSP70; hypoxia; multiple myeloma; proteasome; proteostasis.