Quinn Colin H, Beierle Andee M, Williams Adele P, Marayati Raoud, Bownes Laura V, Markert Hooper R, Aye Jamie M, Stewart Jerry E, Mroczek-Musulman Elizabeth, Crossman David K, Yoon Karina J, Beierle Elizabeth A
Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, 1600 7th Ave. South, Lowder, Room 300, Birmingham, AL 35233, United States.
Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, United States.
Transl Oncol. 2021 Jul;14(7):101099. doi: 10.1016/j.tranon.2021.101099. Epub 2021 Apr 19.
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 downregulation 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.
在研究实体瘤治疗效果时，患者来源的异种移植瘤比长期传代的细胞系具有显著优势。我们实验室遇到了一例来自儿科患者的高级别、转移性、神经内分泌样肿瘤，其具有独特的基因谱。特别是，发现了TYRO3和ALK的突变。我们建立了该肿瘤的人患者来源异种移植瘤系（PDX）用于当前研究。我们研究了克唑替尼的作用，克唑替尼是一种已知能有效靶向TYRO3和ALK突变的化疗药物。克唑替尼通过下调STAT3信号通路有效降低了PDX肿瘤的活力、增殖、生长和转移特性，但PDGFRβ的表达增加。舒尼替尼是一种PDGFRβ的小分子抑制剂，我们单独以及与克唑替尼联合在该PDX中对其进行了研究。舒尼替尼单独使用时可降低体外的活力、增殖和生长，并减少体内肿瘤生长。联合使用时，舒尼替尼能够通过下调ERK 1/2活性和PDGFRβ受体表达克服潜在的克唑替尼诱导的耐药性；因此，体外和体内的肿瘤生长均显著降低。通过使用PDX，有可能确定克唑替尼对该肿瘤疗效较差，并表明靶向PDGFRβ会更有效。这些发现可能适用于其他具有相同基因突变的实体瘤。
