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Glutamine-restricted diets restore sensitivity to KRASG12D inhibitor through the reversal of ANXA1-mediated metabolic reprogramming

ABSTRACT: This study investigates the mechanisms underlying KRASG12D inhibitor resistance and evaluates strategies to enhance treatment sensitivity. Our findings indicate that a glutamine-restricted diet not only reverses KRASG12D inhibitor resistance in PDAC but also achieves durable remission with long-term survival. Mechanistically, KRASG12D inhibitor resistance markedly upregulates ANXA1 expression, which, in turn, promotes its binding to the glutamine-related enzyme GOT1 and stabilizes its expression. Additionally, we find that ANXA1 up-regulation facilitates mitochondrial localization of GLS1, thereby altering glutamine metabolism. These findings highlight ANXA1-mediated glutamine metabolism as a key driver of KRASG12D inhibitor resistance and support glutamine-restricted diets as a potential therapeutic strategy for KRASG12D-mutant pancreatic ductal adenocarcinoma.

INSTRUMENT(S): Liquid Chromatography MS - alternating - hilic

PROVIDER: MTBLS14825 | MetaboLights | 2026-06-27

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS14825_LC-MS_alternating_hilic.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS14825_LC-MS_alternating_hilic_v2_maf.tsv	Tabular
	s_MTBLS14825.txt	Txt

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Bone Stromal Glutamine Renders Tumor cell PARP Inhibitor Resistance

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Impaired redox adaptation through SLC38A5-dependent glutamine metabolism contributes to melatonin-mediated anoikis sensitivity and metastasis suppression in bone cancer

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2018-11-29 | GSE123062 | GEO

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Bone Stromal Glutamine Renders Tumor cell PARP Inhibitor Resistance

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