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AZD 3965 prevents resistance to MET inhibitors

Chronic treatment of cancer cells with tyrosine kinase inhibitors (TKIs) results in metabolic changes that favor increased glycolysis and secretion of lactate.  This is mediated by raised expression of lactate transporters, glycolytic enzymes and negative regulators of the tricarboxylic acid cycle. Increased lactate production induces secretion of hepatocyte growth factors (HGFs) by cancer-associated fibroblasts, non-cancerous cells found in the tumor microenvironment. Raised levels of HGF results in constitutive activation MET in cancer cells that override inhibition by TKIs and leads to resistance. 

 

As lactate secretion mediates adaptive resistance to TKIs, the therapeutic potential of targeting the lactate transporter MCT1 was tested in in vivo models of adaptive resistance to TKIs. Treatment of TKI-resistant tumors with MCT1 inhibitor AZD 3965 from Carbosynth (BA164976) prevented adaptive resistance as well as re-sensitizing tumors with established resistance to TKIs. 

For more information, please refer to the priginal paper: Apicella et al, 2018.

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