Downregulation of PDGFRß Signaling Overcomes Crizotinib Resistance in a TYRO3 and ALK Mutated Neuroendocrine-Like Tumor

被引:6
作者
Quinn, Colin H. [1 ]
Beierle, Andee M. [1 ]
Williams, Adele P. [1 ]
Marayati, Raoud [1 ]
Bownes, Laura V. [1 ]
Markert, Hooper R. [1 ]
Aye, Jamie M. [2 ]
Stewart, Jerry E. [1 ]
Mroczek-Musulman, Elizabeth [3 ]
Crossman, David K. [4 ]
Yoon, Karina J. [5 ]
Beierle, Elizabeth A. [1 ]
机构
[1] Univ Alabama Birmingham, Div Pediat Surg, Dept Surg, 1600 7th Ave South,Room 300, Birmingham, AL 35233 USA
[2] Univ Alabama Birmingham, Dept Pediat, Div Pediat Hematol Oncol, Birmingham, AL 35233 USA
[3] Childrens Hosp Alabama, Dept Pathol, Birmingham, AL 35233 USA
[4] Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35233 USA
[5] Univ Alabama Birmingham, Dept Pharmacol & Toxicol, Birmingham, AL 35233 USA
来源
TRANSLATIONAL ONCOLOGY | 2021年 / 14卷 / 07期
基金
美国国家卫生研究院;
关键词
Targeted therapy; Drug resistance; Crizotinib; Neuroendocrine tumor; Patient derived xenoline; INHIBITOR PF-06463922; CANCER STATISTICS; NPM-ALK; NEUROBLASTOMA; SUNITINIB; THERAPY; AXL; EXPRESSION; DRIVEN; PHOSPHORYLATION;
D O I
10.1016/j.tranon.2021.101099
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Patient-derived xenografts provide significant advantages over long-term passage cell lines when investigating efficacy of treatments for solid tumors. Our laboratory encountered a high-grade, metastatic, neuroendocrine-like tumor from a pediatric patient that presented with a unique genetic profile. In particular, mutations in TYRO3 and ALK were identified. We established a human patient-derived xenoline (PDX) of this tumor for use in the current study. We investigated the effect of crizotinib, a chemotherapeutic known to effectively target both TYRO3 and ALK mutations. Crizotinib effectively decreased viability, proliferation, growth, and the metastatic properties of the PDX tumor through downregulation of STAT3 signaling, but expression of PDGFRss was increased. Sunitinib is a small molecule inhibitor of PDGFRss and was studied in this PDX independently and in combination with crizotinib. Sunitinib alone decreased viability, proliferation, and growth in vitro and decreased tumor growth in vivo. In combination, sunitinib was able to overcome potential crizotinib-induced resistance through down-regulation of ERK 1/2 activity and PDGFRss receptor expression; consequently, tumor growth was significantly decreased both in vitro and in vivo. Through the use of the PDX, it was possible to identify crizotinib as a less effective therapeutic for this tumor and suggest that targeting PDGFRss would be more effective. These findings may translate to other solid tumors that present with the same genetic mutations.
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页数:10
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