The Multi-kinase Inhibitor Debio 0617B Reduces Maintenance and Self-renewal of Primary Human AML CD34+ Stem/Progenitor Cells

  • Mol Cancer Ther. 2017 Aug;16(8):1497-1510. doi: 10.1158/1535-7163.MCT-16-0889.
Maximilien Murone  1 ,  Ramin Radpour  2 ,  Antoine Attinger  1 ,  Anne Vaslin Chessex  1 ,  Anne-Laure Huguenin  2 ,  Christian M Schürch  3 ,  Yara Banz  3 ,  Saumitra Sengupta  4 ,  Michel Aguet  5 ,  Stefania Rigotti  1 ,  Yogeshwar Bachhav  1 ,  Frédéric Massière  1 ,  Murali Ramachandra  4 ,  Andres McAllister  1 ,  Carsten Riether  6  7
Affiliations
  • 1. Debiopharm International S.A., Lausanne, Switzerland.
  • 2. Tumor Immunology, Department of Clinical Research, University of Bern, Bern, Switzerland.
  • 3. Institute of Pathology, University of Bern, Bern, Switzerland.
  • 4. Aurigene Discovery Technologies Limited, Bangalore, Karnataka, India.
  • 5. Swiss Federal Institute of Technology (EPFL), Lausanne, Switzerland.
  • 6. Tumor Immunology, Department of Clinical Research, University of Bern, Bern, Switzerland. [email protected].
  • 7. Department of Medical Oncology, Inselspital, University Hospital and University of Bern, Bern, Switzerland.
PMID: 28468777 DOI: 10.1158/1535-7163.MCT-16-0889
Abstract

Acute myelogenous leukemia (AML) is initiated and maintained by leukemia stem cells (LSC). LSCs are therapy-resistant, cause relapse, and represent a major obstacle for the cure of AML. Resistance to therapy is often mediated by aberrant tyrosine kinase (TK) activation. These TKs primarily activate downstream signaling via STAT3/STAT5. In this study, we analyzed the potential to therapeutically target aberrant TK signaling and to eliminate LSCs via the multi-TK inhibitor Debio 0617B. Debio 0617B has a unique profile targeting key kinases upstream of STAT3/STAT5 signaling such as JAK, Src, ABL, and class III/V receptor TKs. We demonstrate that expression of phospho-STAT3 (pSTAT3) in AML blasts is an independent prognostic factor for overall survival. Furthermore, phospho-STAT5 (pSTAT5) signaling is increased in primary CD34+ AML stem/progenitors. STAT3/STAT5 activation depends on tyrosine phosphorylation, mediated by several upstream TKs. Inhibition of single upstream TKs did not eliminate LSCs. In contrast, the multi-TK inhibitor Debio 0617B reduced maintenance and self-renewal of primary human AML CD34+ stem/progenitor cells in vitro and in xenotransplantation experiments resulting in long-term elimination of human LSCs and leukemia. Therefore, inhibition of multiple TKs upstream of STAT3/5 may result in sustained therapeutic efficacy of targeted therapy in AML and prevent relapses. Mol Cancer Ther; 16(8); 1497-510. ©2017 AACR.

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