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Vol 25, No. 11, November 2021   |   Issue PDF view/purchase
New Strategy to Treat Acute Myeloid Leukaemia: Targeting Chaperone Proteins
The new inhibitor can effectively inhibit the overgrowth of leukaemia cells and shows potential to help overcome drug resistance.

Acute myeloid leukaemia (AML) is generally divided into subtypes based on their appearance and genetic mutation, with some forms of the cancer being more aggressive than others. The FLT3 mutation, for instance, causes a very aggressive form of leukaemia with high chances of relapse even after treatment because it encourages the overgrowth of abnormal leukaemia cells. Unfortunately, 20 to 30 per cent of people with acute myeloid leukaemia have this mutation and many chemotherapy drugs are not completely effective against cancers with the FLT3 mutation. Although FLT3 kinase inhibitors have demonstrated great success in clinical practice, prolonged treatments with the drug can lead to drug-acquired resistance.

Now, scientists led by Professor Liu Qingsong from the Hefei Institutes of Physical Sciences of the Chinese Academy of Sciences have discovered that the Bruton Tyrosine Kinase (BTK) inhibitor QL47 has potent anti-proliferative activity against FLT3-ITD (internal tandem duplication) positive AML cell lines and can induce FLT3-ITD protein degradation.

“What we are seeking is a new therapeutic strategy which imperative for FLT3-ITD-positive AML,” said Hu Chen, lead author of the study.

Heat shock proteins are major players in protein homeostasis and folding, especially for the overexpressed or mutated oncoproteins in cancers. Therefore, the team examined the interactions between QL47 and heat shock proteins. Surprisingly, QL47 was able to act on the heat shock protein HSP70. Through further study, the team was able to prove how QL47 works: the inhibitor irreversibly binds to heat shock protein HSP70 and inhibits its refolding activity, which in turn leads to the degradation of FLT3-ITD and suppresses the proliferation of FLT3-ITD positive AML cells.

“It is inducible HSP70 instead of constitutive expressed HSC70 that is important for FLT3 protein stabilisation and FLT3-ITD-positive cell viability,” revealed Dr. Hu.

Using primary patient cells and in vivo tumour models, the scientists evaluated the effects of QL47 from which they found that QL47 induced the degeneration of FLT3-ITD protein and cell apoptosis in primary patient cells. In a mice bone marrow engraftment model, QL47 significantly extended the survival of the animals. With this newly discovered HSP70 inhibitor and its potent antitumor efficacy, Dr. Hu believes that the QL47 “could potentially provide a novel strategy for FLT3-ITD-positive AML treatment” and overcome drug resistance.

Source: Hu et al. (2021). Targeting chaperon protein HSP70 as a novel therapeutic strategy for FLT3-ITD-positive acute myeloid leukemia. Signal Transduction and Targeted Therapy, 6, 334.

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