WCLC 2025 - Posters & ePosters-P2.02.30 Targeting MTA2 Lactylation as a Therapeutic Strategy to Overcome Chemoresistance in Lung Adenocarcinoma

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This study explores the role of lactylation, a metabolite-derived post-translational modification, in chemotherapy resistance in lung adenocarcinoma (LUAD). Chemoresistance remains a critical barrier to effective LUAD treatment, as cancer cells adapt to withstand DNA damage induced by conventional chemotherapy agents like cisplatin. Using metabolomic profiling and metabolite library screening of drug-resistant LUAD cells, researchers identified lactate and lactic acid as key metabolites associated with cisplatin resistance.<br /><br />Mass spectrometry-based lactylome analysis revealed that MTA2, a chromatin remodeling protein, undergoes lactylation at the lysine 539 residue (MTA2-K539la) specifically upon cisplatin treatment. This modification was shown to enhance MTA2 protein stability and influence its biophysical properties via regulating liquid–liquid phase separation, a process implicated in controlling protein dynamics and function. Functional assays, including immunofluorescence, cycloheximide chase, fluorescence recovery after photobleaching (FRAP), and in vitro droplet formation, confirmed that lactylation at MTA2-K539 stabilizes the protein and promotes chemoresistance by mitigating DNA damage responses.<br /><br />Importantly, the study developed a novel cell-penetrating peptide (CPP) targeting the MTA2-K539la site (K539-Pep), which specifically inhibits this lactylation modification. Treatment with K539-Pep sensitized LUAD cells to cisplatin, increased DNA damage as shown by comet assays, and diminished cell viability under chemotherapy. These findings position MTA2-K539 lactylation as a driver of chemoresistance and highlight targeting this modification with a CPP as a promising therapeutic strategy to overcome drug resistance in LUAD.<br /><br />In summary, this work presents the first identification of MTA2-K539 lactylation in lung cancer, elucidates its role in chemotherapy resistance through phase separation regulation, and offers a novel peptide-based approach to enhance chemosensitivity, thereby advancing treatment options for LUAD patients.

Asset Subtitle

Ren Shencheng

Meta Tag

Speaker Ren Shencheng

Topic Tumor Biology – Preclinical Biology

Keywords

lactylation

chemotherapy resistance

lung adenocarcinoma

MTA2 protein

lysine 539 modification

liquid–liquid phase separation

cisplatin resistance

cell-penetrating peptide

DNA damage response

chemosensitivity enhancement