伊马替尼
舒尼替尼
主旨
癌症研究
酪氨酸激酶
酪氨酸激酶抑制剂
甲磺酸伊马替尼
MAPK/ERK通路
PDGFRA公司
受体酪氨酸激酶
靶向治疗
生物
医学
间质细胞
信号转导
癌症
内科学
细胞生物学
髓系白血病
作者
Salomé Ruiz-Demoulin,Eva Trenquier,Sanaa Dekkar,Sébastien Deshayes,Prisca Boisguérin,César Serrano,Pascal de Santa Barbara,Sandrine Faure
摘要
Gastrointestinal stromal tumor (GIST), the most common sarcoma, is mainly caused by an oncogenic mutation in the KIT receptor tyrosine kinase. Targeting KIT using tyrosine kinase inhibitors, such as imatinib and sunitinib, provides substantial benefit; however, in most patients, the disease will eventually progress due to KIT secondary mutations leading to treatment failure. Understanding how GIST cells initially adapt to KIT inhibition should guide the selection of appropriate therapies to overcome the emergence of resistance. Several mechanisms have been broadly implicated in the resistance to imatinib anti-tumoral effects, including the reactivation of MAPK signaling upon KIT/PDGFRA targeted inhibition. This study provides evidence that LImb eXpression 1 (LIX1), a protein we identified as a regulator of the Hippo transducers YAP1 and TAZ, is upregulated upon imatinib or sunitinib treatment. LIX1 silencing in GIST-T1 cells impaired imatinib-induced MAPK signaling reactivation and enhanced imatinib anti-tumor effect. Our findings identified LIX1 as a key regulator of the early adaptative response of GIST cells to targeted therapies.
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