Eukaryote initiation factor 6 modulates small-cell lung carcinoma plasticity via the integrin-FAK signaling axis
The translation initiation factor eIF6 is a critical regulator of non‑NE transdifferentiation in small cell lung carcinoma via its interaction with the CD104‑FAK complex, leading to MAPK pathway activation; targeting eIF6 suppresses non‑NE transdifferentiation and improves chemotherapy sensitivity.
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.
Understanding eIF6-mediated plasticity provides a therapeutic target to overcome chemoresistance in SCLC.
Evidence level: Klinikai vizsgálat. Formális klinikai vizsgálati eredmény.
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