LKB1-dependent regulation of TPI1 creates a divergent metabolic liability between human and mouse lung adenocarcinoma.

Overview

KRAS is the most frequently mutated oncogene in human lung adenocarcinomas (hLUAD) 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 (mLUAD). Here we provide a mechanistic explanation for this difference by uncovering an evolutionary divergence in regulation of triosephosphate isomerase (TPI1). In hLUAD, TPI1 activity is regulated via phosphorylation at Ser21 by the Salt Inducible Kinases (SIKs) 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. Our findings suggest this metabolic flexibility is critical in rapidly growing cells with KRAS and TP53 mutations, explaining why loss of LKB1 creates a liability in these tumors.