HSP90 Inhibitors Selectively Target FLT3-ITD-driven Acute Myeloid Leukemia and Bypass TKI Resistance

Jorrit Enserink, Groupleader, Cancer Molecular Medicine, Oslo University Hospital and professor II, Department of Biosciences, University of Oslo.

Jorrit Enserink. Photo: www.ous-research.no

Activating mutations in the gene encoding the receptor tyrosine kinase FLT3, particularly internal tandem duplications in the receptor’s juxtamembrane domain (FLT3-ITD), are the most common lesions found in acute myeloid leukemia (AML) and are associated with inferior clinical outcome. The cellular pathways that support FLT3-ITD-driven cell proliferation and survival remain poorly understood. We discovered an FLT3-ITD-specific protein interaction network that contain multiple HSP90 family proteins, including GRP94. We show that GRP94 is responsible for retaining immature FLT3-ITD in the ER, where it aberrantly activates several downstream pathways. Specific inhibition of GRP94 results in translocation of FLT3-ITD from the ER to the cell membrane, uncoupling FLT3-ITD from the STAT5 and b-catenin pathways, whereas broad-range HSP90 inhibitors also induce degradation of FLT3-ITD. HSP90 proteins prevent apoptosis of FLT3-ITD-expressing cells by ameliorating proteotoxic stress and by suppressing generation of toxic ROS levels. Importantly, HSP90 inhibitors specifically sensitize FLT3-ITD-expressing bone marrow-derived cells for TKIs, whereas cells derived from healthy donors are unaffected. HSP90 inhibitors also preferentially eradicate a population of patient-derived FLT3-ITD+ AML cells expressing leukemic stem cell markers. Taken together, our study reveals a molecular basis for HSP90 addiction of FLT3-ITD-driven AML and provides a rationale for treatment of this form of AML with HSP90 inhibitors.

Published Apr. 29, 2017 11:07 AM - Last modified May 1, 2017 9:01 PM