Differences in animal biology can affect cancer drug development WeillCornell
KRAS is the most frequently mutated oncogene in human lung adenocarcinomas and activating mutations frequently co-occur with loss-of-function mutations in TP53 or STK11/LKB1. However, mutation of all three genes is rarely observed in hLUAD, even though engineered co-mutation is highly aggressive in mouse lung adenocarcinoma . Here we provide a mechanistic explanation for this difference by uncovering an evolutionary divergence in regulation of triosephosphate isomerase .
In hLUAD, TPI1 activity is regulated via phosphorylation at Ser21 by the Salt Inducible Kinases in an LKB1-dependent manner, modulating flux between completion of glycolysis and production of glycerol lipids. In mice, Ser21 of TPI1 is a Cys residue which can be oxidized to alter TPI1 activity without a need for SIKs or LKB1.
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