Mycoplasma infection drives EGFR-TKI resistance through convergent transcriptomic reprogramming in non-small cell lung cancer.

Authors

Bing Wang, Valentina Donati, Alessandro Gregori, Alessandro Leonetti, Aldo Pastore, Dongmei Deng, Elisa Giovannetti

Published in

iScience. Volume 29. Issue 8. Pages 116999. Aug 21, 2026. Epub Jul 31, 2026.

Abstract

Epidermal growth factor receptor (EGFR) mutations are an oncogenic driver in non-small cell lung cancer (NSCLC), but resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major challenge. Here, we show that mycoplasma infection sustains ERK, AKT, and NF-κB signaling; impairs receptor internalization; and reduces osimertinib sensitivity in EGFR-mutant NSCLC cells. Antibiotic-mediated clearance of Mycoplasma partially restored drug sensitivity, establishing a causal infection-resistance link. Transcriptomic analysis identified converging pathways related to mycoplasma infection and drug resistance, including gene sets enriched for inhibition of receptor internalization and clathrin downregulation at the protein level. Combined inhibition of mTOR and LDHA improved growth suppression in mycoplasma-positive cells. Clinically, mycoplasma infection and higher LDHA expression were associated with poor overall survival of EGFR-TKI-treated patients. These findings establish mycoplasma infection as a causal, non-genetic contributor to EGFR-TKI resistance and support a hierarchical therapeutic strategy combining antibiotic eradication with mTOR and LDHA inhibition.

PMID:
42572587
Bibliographic data and abstract were imported from PubMed on 10 Aug 2026.

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