【摘 要】
：
Background: Like T315I Bcr-Abl, T674I FIP1L1-PDGFRα existed in a subset of chronic eosinophilic leukemia (CEL) is also gatekeeper mutation that is resistant to tyrosine kinase inhibitors (TKIs, e.g.,
【机 构】
：
Department of Pathophysiology,Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou,China;Ke
【出 处】
：
2014医学科学前沿暨第三届个体化治疗与抗肿瘤药物研究新趋向研讨会
论文部分内容阅读
Background: Like T315I Bcr-Abl, T674I FIP1L1-PDGFRα existed in a subset of chronic eosinophilic leukemia (CEL) is also gatekeeper mutation that is resistant to tyrosine kinase inhibitors (TKIs, e.g., imatinib, nilotinib and dasatinib) approved by FDA.Therefore, novel TKIs against T674I FIP1L1-PDGFRα are still needed.Ponatinib is a novel orally bioavailable TKI against T315I Bcr-Abl.But it is not clear whether ponatinib is effective against T674I FIP1L1-PDGFRα.The purpose of this study was to examine the effect ofponatinib on T674I FIP1L1-PDGFRα.Methods: Molecular docking analysis in silico was first performed.The effects of ponatinib on PDGFRα signaling pathways, apoptosis and cell cycling were examined in EOL-1, BaF3 cells expressing either wild type (WT) or T674I FIP1L1-PDGFRα.The in vivo antitumor activity of ponatinib was measured with xenografted BaF3-T674I FIP1L1-PDGFRα cells in nude mice models.Results: Molecular docking analysis in silico revealed that ponatinib could bind to the DFG (Asp-Phe-Gly)-out state of T674I PDGFRα.Ponatinib potently inhibited the phosphorylation of WT and T674I FIP1L1-PDGFRα and their downstream signaling molecules (e.g., Stat3, Stat5).Ponatinib strikingly inhibited the growth of both WT and T674I FIP1L1-PDGFRα-carrying CEL cells.It induced apoptosis in CEL cells with caspase-3-dependent cleavage of Mcl-1, and inhibited tyrosine phosphorylation of β-catenin to decrease its stability and pro-survival functions.In vivo, ponatinib abrogated the growth of xenografted BaF3-T674I FIP1L1-PDGFRα cells in nude mice.Conclusions: Ponatinib is a pan-FIP1L1-PDGFRα inhibitor, and clinical trials are warranted to investigate its efficacy in imatinib-resistant CEL.
其他文献
Our previous study demonstrated that COX-2 selective inhibitor celecoxib antagonized the cytotoxic action of cisplatin and carboplatin through COX-2-independent mechanisms.Whether celecoxib also affec
The ABCB1 transporter is one of the members of ATP-binding cassette superfamilies,frequently overexpressed in cancer cells and leads to multidrug resistance (MDR).Over-expressing of ABCB1 in cancer ce
Background: Protein Tyrosine Phosphatase Receptor-type O (PTPRO) has recently been in the spotlight as a tumor suppressor, whose encoding gene is frequently methylated in cancers.We examined the methy
Gastroesophageal junction (GEJ) adenocarcinoma is a lethal cancer with rising incidence, yet the molecular biomarkers that have strong prognostic impact and also hold great therapeutic promise remain
Gastroesophageal junction adenocarcinoma (GEJA) is an aggressive malignancy with an alarmingly rising incidence.TNM staging is widely used by oncologists to stratify prognosis as well as direct therap
Gliomas are the most common and malignant primary brain tumors with a poor prognosis despite multiple therapies.Quercetin, a traditional Chinese medicinal herb,is an important flavonoid with the anti-
Background: Cervical cancer is the third most common malignancy in women worldwide, and it remains a leading cause of cancer-related death for women in developing countries.Though high-risk human papi
MicroRNAs (miRNAs) play essential roles in the progression of osteosarcoma.Interestingly, though, the expression level of miR-377 is lower in 7 osteosarcoma samples than in normal human osteoblasts; t