A signal in resistant tumors
A lactate-related change to the HER2 protein may help explain why some gastric cancers become less responsive to trastuzumab, researchers report. The work focused on a chemical mark called lactylation, in which a lactate-related group is attached to a protein. The key site was lysine 1171, written as K1171. In tumor tissues later classified as trastuzumab-resistant, lactate was among the most abundant metabolites, and the resistant samples had higher lactate and pan-lactylation, a broad measure of this type of protein marking. Tumors with high lactate also had higher HER2 protein expression.
The tissue comparison was small: untargeted metabolomics used six surgically resected tumors from patients later classified as resistant and six from patients later classified as sensitive after treatment. That design allowed the researchers to look for a biochemical pattern associated with later treatment response. It did not, by itself, show that lactate or HER2 lactylation caused resistance. The study paired the tissue analysis with laboratory experiments involving cells and purified proteins.
Following the trail to HER2
To identify the factor involved, the researchers used immunoaffinity purification with liquid chromatography tandem mass spectrometry, or LC-MS/MS, followed by co-immunoprecipitation validation and an in vitro assay with purified recombinant HER2. The work identified AARS1 as a protein involved in the mechanism under study. In the tested cells, NALA treatment and raising AARS1 levels were associated with increased HER2 K1171 lactylation. An LDH inhibitor, or reducing AARS1, was associated with lower levels.
A telling comparison came from changing the K1171 site itself. When lysine at that position was replaced with arginine, creating the K1171R version of HER2, the interventions changed wild-type HER2 protein but did not change the mutant in the reported cell experiments. NALA was associated with higher wild-type HER2 protein, while LDH inhibition was associated with lower wild-type protein. AARS1 overexpression, AARS1 knockdown and L-alanine showed the same wild-type-versus-mutant pattern. The pattern is consistent with K1171 being tied to HER2 stability in these models, although the supplied results do not provide numerical effect sizes or confidence intervals.
A second receptor enters the picture
The researchers then examined USP11, a protein that bound to HER2 in their experiments. The K1171R mutant showed less USP11 binding than wild-type HER2, and raising USP11 levels increased wild-type HER2 protein but not the mutant. The authors interpret this pattern as evidence that the K1171 state is tied to HER2 stability through USP11. But the study did not resolve the structural basis of that interaction.
The pattern extended to HER2 binding with EGFR. NALA was associated with stronger HER2-EGFR binding, while LDH inhibition and L-alanine were associated with weaker binding. NALA did not increase EGFR binding to the K1171R mutant. The same site therefore appeared to track with both HER2 protein changes and the receptor pairing tested by the researchers.
Taken together, the findings outline a testable sequence of associations: lactate-related signals were higher in resistant tumor tissues; AARS1 and the K1171 site were tied to HER2 lactylation and protein abundance in cells; and the K1171 state tracked with binding to USP11 and EGFR. The evidence is preclinical, not proof that changing this pathway will help patients. The human tissue results are observational, and the study did not test a treatment in patients. The findings point to a research direction rather than a treatment now shown to work.
Paper data and sources
Original title: Lactylation‐Mediated HER2 Stabilization Promotes Trastuzumab Resistance in Gastric Cancer
Authors: Qian M, Tian T, Wang Z et al.
Journal/Repository: Advanced Science
Status: Peer-reviewed
First online: 2026-10-11
DOI: Not available
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