LKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung Adenocarcinoma.

TitleLKB1-Dependent Regulation of TPI1 Creates a Divergent Metabolic Liability between Human and Mouse Lung Adenocarcinoma.
Publication TypeJournal Article
Year of Publication2023
AuthorsStein BD, Ferrarone JR, Gardner EE, Chang JWon, Wu D, Hollstein PE, Liang RJ, Yuan M, Chen Q, Coukos JS, Sindelar M, Ngo B, Gross SS, Shaw RJ, Zhang C, Asara JM, Moellering RE, Varmus H, Cantley LC
JournalCancer Discov
Date Published2023 Apr 03
KeywordsAdenocarcinoma of Lung, Animals, Humans, Lung Neoplasms, Mice, Mutation, Protein Serine-Threonine Kinases, Proto-Oncogene Proteins p21(ras), Triose-Phosphate Isomerase

UNLABELLED: 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 comutation is highly aggressive in mouse lung adenocarcinoma (mLUAD). Here, we provide a mechanistic explanation for this difference by uncovering an evolutionary divergence in the regulation of triosephosphate isomerase (TPI1). In hLUAD, TPI1 activity is regulated via phosphorylation at Ser21 by the salt inducible kinases (SIK) in an LKB1-dependent manner, modulating flux between the completion of glycolysis and production of glycerol lipids. In mice, Ser21 of TPI1 is a Cys residue that 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 the loss of LKB1 creates a liability in these tumors.

SIGNIFICANCE: Utilizing phosphoproteomics and metabolomics in genetically engineered human cell lines and genetically engineered mouse models (GEMM), we uncover an evolutionary divergence in metabolic regulation within a clinically relevant genotype of human LUAD with therapeutic implications. Our data provide a cautionary example of the limits of GEMMs as tools to study human diseases such as cancers. This article is highlighted in the In This Issue feature, p. 799.

Alternate JournalCancer Discov
PubMed ID36715544
PubMed Central IDPMC10068449
Grant ListR01 AR076029 / AR / NIAMS NIH HHS / United States
R21 ES032347 / ES / NIEHS NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
T32 GM007281 / GM / NIGMS NIH HHS / United States
R01 DK080425 / DK / NIDDK NIH HHS / United States
F99 CA234950 / CA / NCI NIH HHS / United States
P30 CA014195 / CA / NCI NIH HHS / United States
R35 CA197588 / CA / NCI NIH HHS / United States
R35 CA220538 / CA / NCI NIH HHS / United States
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