EIF6 conditions drug-tolerant persister-like transdifferentiation in small cell lung carcinoma

Author:

Shen Shensi1ORCID,Peng Haoning1ORCID,Wang Zhile2ORCID,Wang Mengyao1,Tang Xinpu1,Li Kaixiu1,Yu Xuejiao1,Song Siyang1,Wang Yuqing1,Lu Tianjian1,Dong Bo1,Wang Youyu2,Chen Minqi2,Ceng Dongjian3,Deng Yulan3,Xia Liang3,Guo Chenglin3,Pu Qiang4,Li Lu5,Cerezo Michael6ORCID,Wang Weiya1,Liu Lunxu1

Affiliation:

1. West China hospital, Sichuan University

2. Sichuan University

3. West China hospital,Sichuan University

4. West China Medical Center

5. Lung Cancer Center, West china Hospital, Sichuan University

6. INSERM, U1065, Equipe 12, Centre Méditerranéen de Médecine Moléculaire

Abstract

Abstract

Drug-tolerant persister cells withstand treatments by adapting their identity through lineage-dependent plasticity during systemic anti-cancer therapies. This phenomenon is evident in small-cell lung carcinoma (SCLC), a lethal neuroendocrine cancer initially responsive (60-80%) to platinum-based chemotherapy but succumbing to resistance within 6 months in advanced stages. This resistance associates with the transdifferentiation of residual tumour cells into a non-neuroendocrine state, a process intricately tied to SCLC's chemotolerance, yet molecular mechanisms governing this lineage conversion remain completed understood. Here we report that first-line chemotherapy induces translation initiation factor eIF6 in drug-tolerant persister-like cells in SCLC, associating with the non-neuroendocrine state in both SCLC genetically engineered mouse model and patient samples. Intervening eIF6 inhibits non-neuroendocrine transdifferentiation, thus enhancing SCLC responsiveness to chemotherapy. Mechanistically, therapy-induced eIF6 dissociates from ribosomes whereas interacts with the extracellular matrix complex CD104/FAK, leading to the activation of MAPK pathway and a global translational remodelling in SCLC drug-tolerant persister-like cells. This prompts us to develop an eIF6-CD104/FAK proximity ligation assay applicable to clinical samples, showing its prognostic value for SCLC clinical outcomes. This study of eIF6’s moonlight function sheds light on its potential therapeutic interventions to mitigate treatment resistance in SCLC.

Publisher

Research Square Platform LLC

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