Activation of the NF-κB/ALDH1A1 Signaling Promotes Non-Mutational Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer

ABSTRACT: Acquired resistance to tyrosine kinase inhibitors (TKIs) remains a major clinical challenge in the treatment of EGFR-mutant non-small cell lung cancer (NSCLC). This study established TKI-resistant variants by integrating cell lines, lung cancer organoids (LCOs), and in vivo models, revealing the pivotal role of the NF-κB/ALDH1A1 signaling in mediating non-mutational TKI resistance. Resistant cells exhibited elevated RELA phosphorylation, enhanced ALDH1A1 expression and enzymatic activity, and stem-like properties. Mechanistically, NF-κB activation occurred as an early response to TKI exposure and promoted ALDH1A1 transcription via RELA. In turn, ALDH1A1 contributed to the sustained activation of NF-κB signaling, forming a self-reinforcing positive feedback loop.. Genetic ALDH1A1 or RELA silencing reversed the resistant phenotype. Pharmacologically, treatment with an EGFR-TKI and the ALDH1A1 inhibitor disulfiram or the NF-κB-targeting agent EGCG synergistically restored the antitumor efficacy of TKIs both in vitro and in vivo. These findings establish the NF-κB/ALDH1A1 signaling as a key non-genetic mechanism of acquired EGFR-TKI resistance and provide a rational combination strategy to overcome it.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324066 | GEO | 2026/10/01

REPOSITORIES: GEO