Pharmacologic inhibition of AKT leads to cell death in relapsed multiple myeloma

• Published in: Cancer letters 2018-09, Vol.432, p.205-215
• Main Authors: Song, In-Sung, Jeong, Yu Jeong, Jeong, Seung Hun, Kim, Hyoung Kyu, Ha, Nam-Chul, Shin, MyungGeun, Ko, Kyung Soo, Rhee, Byoung Doo, Shim, Sungbo, Jang, Sung-Wuk, Han, Jin
• Format: Article
• Language: English
• Subjects: AKT; AKT protein; Anti-Cancer drug; Apoptosis; Cancer therapies; Cell death; Clinical significance; Computed tomography; Cytotoxicity; Drug resistance; Genes; Heat shock proteins; HS1793; HSP90; Hsp90 protein; Immunoglobulins; Kinases; Lymphocytes B; Metabolism; Metastases; Metastasis; Mitochondria; Multiple myeloma; Pathophysiology; Phosphoprotein phosphatase; Phosphorylation; Plasmids; Protein phosphatase; Therapeutic applications; Tomography; Transcription
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.06.020

Multiple myeloma (MM) is a neoplastic plasma cell disorder with high disease recurrence rates. Novel therapeutic approaches capable of improving outcomes in patients with MM are urgently required. The AKT signalling plays a critical regulatory role in MM pathophysiology, including survival, proliferation, metabolism, and has emerged as a key therapeutic target. Here, we identified a novel AKT inhibitor, HS1793, and defined its mechanism of action and clinical significance in MM. HS1793 disrupted the interaction between AKT and heat shock protein 90, resulting in protein phosphatase 2A-modulated phosphorylated-AKT (p-AKT) reduction. Moreover, we observed reductions in the kinase activity of the AKT downstream target, IκB kinase alpha, and the transcriptional activity of nuclear factor kappa B, which induced mitochondria-mediated cell death in MM cells exclusively. We confirmed the cytotoxicity and specificity of HS1793 via PET-CT imaging of a metastatic mouse model generated using human MM cells. We also evaluated the cytotoxic effects of HS1793 in primary and relapsed MM cells isolated from patients. Thus, HS1793 offers great promise in eliminating MM cells and improving therapeutic responses in primary and relapsed/refractory MM patients. •HS1793 suppresses AKT-HSP90 binding leading to AKT inactivation.•Suppression of AKT-HSP90 binding result in the IKK/NF-κB pathway inhibition.•HS1793 induces relapsed MM cell death, and decreases bone metastasis.