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

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Acute lymphoblastic leukemia (ALL) is a group of malignant disorders affecting the blood and blood-forming tissues in the bone marrow, lymphatic system, and spleen. ALL is broadly classified by which types of lymphocytes are affected. B-cell ALL affects B lymphocytes, cells that are produced and mature in the bone marrow and represents respectively 75% of cases. T-cell ALL affects T lymphocytes and represents 25% of cases. Although ALL therapy has shown remarkable improvements in recent years, however, a high percentage of adult patients with ALL still experience relapse. Therefore, it was necessary to discover new treatment strategies that would improve the prognosis of patients after a relapse.

Given the crucial role of Src in tumor development and extensive preclinical evidence of metastasis suppression by Src inhibition, several clinically applicable small molecule Src inhibitors like Dasatinib and Saracatinib , have been developed and they have been found to be able to suppress in vitro and in vivo cell proliferation of ALL cells.

Our recent study showed that HSP90, a heat shock protein known to facilitate the maturation, stabilization and activation of over 200 client proteins, is overexpressed in ALL cells compared with resting B and T cells. Moreover, we showed that HSP90 overexpression is accompanied by an overexpression of LYN kinase in B-ALL and LCK kinase in T-ALL. In the paper just published in BCJ ,we found that HSP90 is an important regulator of SRC kinases(LCK and LYN), which are involved in the intracellular signaling pathways necessary for the growth and proliferation of T-ALL, B-ALL and other types of leukemic cells. We showed that HSP90 inhibition by NVP-BEP800 induces dissociation of the aberrant HSP90-LYN complex in B-ALL cells and disrupts the entire BCR signaling pathway. LYN and NFϰB lose phosphorylation and become inactive, and the latter leave the nucleus, which leads to inhibition of the survival, growth and maintenance of B-ALL cells. We also showed that in T-ALL cells, after treatment with NVP-BEP800, the calcium / NFAT pathway was inactivated, and LCK lost its phosphorylation, whereas NFAT1 becomes phosphorylated upon inactivation and leaves the nucleus leading to inhibition of survival, growth and maintenance of T-ALL cells.

 

 

rmshaik

PhD student, Inserm U1231