HSP90 inhibitor NVP-BEP800 affects stability of SRC kinases and growth of T-cell and B-cell acute lymphoblastic leukemias

Blood Cancer J. 2021 Mar 18;11(3):61. doi: 10.1038/s41408-021-00450-2.

Abstract

T-cell and B-cell acute lymphoblastic leukemias (T-ALL, B-ALL) are aggressive hematological malignancies characterized by an accumulation of immature T- or B-cells. Although patient outcomes have improved, novel targeted therapies are needed to reduce the intensity of chemotherapy and improve the prognosis of high-risk patients. Using cell lines, primary cells and patient-derived xenograft (PDX) models, we demonstrate that ALL cells viability is sensitive to NVP-BEP800, an ATP-competitive inhibitor of Heat shock protein 90 (HSP90). Furthermore, we reveal that lymphocyte-specific SRC family kinases (SFK) are important clients of the HSP90 chaperone in ALL. When PDX mice are treated with NVP-BEP800, we found that there is a decrease in ALL progression. Together, these results demonstrate that the chaperoning of SFK by HSP90 is involved in the growth of ALL. These novel findings provide an alternative approach to target SRC kinases and could be used for the development of new treatment strategies for ALL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Enzyme Stability / drug effects
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Tumor Cells, Cultured
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / metabolism*

Substances

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • NVP-BEP800
  • Pyrimidines
  • src-Family Kinases