SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer

Autor: Ji Zhou, Xu-Chao Zhang, Shan Xue, Mengdi Dai, Yueliang Wang, Xia Peng, Jianjiao Chen, Xinyi Wang, Yanyan Shen, Hui Qin, Bi Chen, Yu Zheng, Xiwen Gao, Zuoquan Xie, Jian Ding, Handong Jiang, Yi-Long Wu, Meiyu Geng, Jing Ai
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Signal Transduction and Targeted Therapy, Vol 8, Iss 1, Pp 1-13 (2023)
Druh dokumentu: article
ISSN: 2059-3635
DOI: 10.1038/s41392-023-01403-w
Popis: Abstract Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer (NSCLC) patients according to the predicted response to c-Met inhibitors (c-Metis), yet the overall clinical benefit of this strategy is quite limited. Notably, c-Met protein overexpression, which occurs in approximately 20–25% of NSCLC patients, has not yet been clearly defined as a clinically useful biomarker. An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking. Herein, we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status. Furthermore, TGF-β1 treatment resulted in SYK transcriptional downregulation, increased Sp1-mediated transcription of FRA1, and restored the mesenchymal state, which conferred resistance to c-Metis. Clinically, a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3% and longer progression-free survival with c-Meti treatment than other patients. SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance. In summary, SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state. Furthermore, our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.
Databáze: Directory of Open Access Journals
Externí odkaz: