Targeting HSP 90 Induces Apoptosis and Inhibits Critical Survival and Proliferation Pathways in Multiple Myeloma

Abstract

The second most commonly diagnosed hematologic malignancy, multiple myeloma, affects predominantly older patients (>60s) and is characterized by paraprotein in the serum or urine. Clinical manifestations include anemia, hypercalcaemia, progressive renal impairment, and osteolytic bone destruction. Despite promising new therapies, multiple myeloma eventually relapses in almost all patients. HSP are ubiquitous and highly conserved in prokaryotes and eukaryote organisms. Exposure to a broad range of stimuli results in increased HSP protein expression. These chaperone proteins are involved in protein transportation, prevent protein aggregation, and ensure correct folding of nascent and stress-accumulated misfolded proteins. In cancer, HSP expression is dysregulated, resulting in elevated expression, which promotes cancer by preventing programmed cell death and supporting autonomous cells growth, ultimately leading to resistance to heat, chemotherapy, and other stresses. Client proteins of HSP90 such as AKT, p53, MEK, STAT3, and Bcr-Abl are vital in tumor progression, including multiple myeloma, and their maturation and stability is dependent on HSP90. Therefore, inhibition of HSP90 via a HSP90 inhibitor (such as NVP-HSP990) should interrupt multiple signaling pathways essential for oncogenesis and growth in multiple myeloma. Our study showed that NVP-HSP990 triggered apoptosis in a panel of human multiple myeloma cells, induced cell-cycle arrest, PARP cleavage, downregulation of client proteins, the inability to reactivate phospho-STAT3 following exogenous IL-6 stimulation, and it synergized with azacytidine and bortezomib in cell lines and primary multiple myeloma samples. The mechanism of HSP90 inhibition in multiple myeloma warrants further evaluation.

Endoplasmic Reticulum Stress and the Unfolded Protein Response: Targeting the Achilles Heel of Multiple Myeloma

“…Proteasome inhibition may increase the requirement for molecular chaperones to maintain accumulating proteins in a soluble state and vice versa inhibition of molecular chaperones may lead to an increase in misfolded proteins that require degradation by the proteasome. In line with this, HSP90 inhibition showed synergistic antimyeloma activity in combination with bortezomib in multiple myeloma cell lines as well as in mouse models (55)(56)(57)(58). A combination of bortezomib with the HSP90 inhibitor tanespimycin (Fig.…”

DangER: protein ovERload. Targeting protein degradation to treat myeloma

“…This was associated with downregulation of 'client' proteins (IL-6R, MEK and Akt) and subsequent upregulation of HSP70 and HSP27. 98 SNX-2112, which exists as a pro-drug SNX-5422, was able to induce cytotoxicity and cell cycle arrest in myeloma cell lines and patient samples. Downregulation of Akt and ERK pathways was demonstrated and, importantly, maintained in the presence of extracellular cytokines.…”

Molecular Pathways: Targeting Hsp90—Who Benefits and Who Does Not

“…Inhibition of the Hsp90 cycle has been shown to have synergistic activity in combination with proteasome inhibitors in the management of patients suffering from multiple myeloma (64,65). In an open label phase I/II trial, Richardson and colleagues (66) reported an overall response rate of 27% with a complete response rate of 3% on a cohort of 63 patients with relapsed or relapsed and refractory multiple myeloma who received a combination of tanespimycin and the proteasome inhibitor bortezomib.…”