Eukaryote initiation factor 6 modulates small-cell lung carcinoma plasticity via the integrin-FAK signaling axis

Small cell lung carcinoma (SCLC) is an aggressive neuroendocrine cancer that rapidly develops resistance to platinum-based chemotherapy. A key feature of SCLC is its ability to switch between neuroendocrine (NE) and non-neuroendocrine (non-NE) states, a process linked to therapeutic failure, yet the underlying mechanisms driving this plasticity remain incompletely understood. Here, we show that the translation initiation factor eIF6 is a critical regulator of non-NE transdifferentiation in SCLC. eIF6 expression is consistently upregulated in non-NE states across cell lines, mouse models, and patient samples, accompanied by global remodelling of the translational landscape. Mechanistically, eIF6 dissociates from ribosomes and interacts with the CD104-FAK complex, leading to MAPK pathway activation. Intervening eIF6 suppresses non-NE transdifferentiation and enhances SCLC chemotherapy sensitivity in vitro and in vivo. These findings position the eIF6-CD104-FAK axis as a prognostic marker and therapeutic target, offering a potential strategy to mitigate SCLC resistance.

Recommended citation: Haoning Peng^#, Zhile Wang^#, Mengyao Wang^#, Zheyu Ding, Kaixiu Li, Yuqing Wang, Xuejiao Yu, Siyang Song, Yulan Deng, Yi Liu, Qiang Pu, Lu Li, Michael Cerezo, Weiya Wang, Lunxu Liu^*, and Shensi Shen^*. 2026. "Eukaryote initiation factor 6 modulates small-cell lung carcinoma plasticity via the integrin-FAK signaling axis." Nature Communications. doi: 10.1038/s41467-026-69899-8.
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