Instituto de Biología y Medicina Experimental (IBYME), CONICET, Buenos Aires, Argentina.
Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Curr Cancer Drug Targets. 2018;18(10):979-987. doi: 10.2174/1568009618666171214114706.
Endocrine resistance and metastatic dissemination comprise major clinical challenges for breast cancer treatment. The fibroblast growth factor receptor family (FGFR) consists of four tyrosine kinase transmembrane receptors, involved in key biological processes. Genomic alterations in FGFR have been identified in advanced breast cancer and thus, FGFR are an attractive therapeutic target. However, the efficacy of FGFR inhibitors on in vivo tumor growth is still controversial.
The purpose of this study was to evaluate the role of FGFR in tumor growth and breast cancer progression.
Cell proliferation was assessed by 3H-thymidine uptake and cell counting in primary cultures of endocrine resistant mammary carcinomas and a human cell line, respectively. Tumor transplants and cell injections were used to determine in vivo growth and spontaneous metastasis. FGFR1-3 and αSMA expression were evaluated on primary tumors by immunohistochemistry.
Antiprogestin resistant murine transplants and a human xenograft express high levels of total FGFR1-3. In vitro treatment with the FGFR inhibitor, BGJ398, impaired cell proliferation of resistant variants versus vehicle. In vivo, versus control, BGJ398 treatment decreased one out of four resistant tumors, however all tumors showed a decreased epithelial/stromal ratio. Finally, in a model of hormone resistant mammary cancer that spontaneously metastasizes to the lung, BGJ398 decreased the number of mice with lung metastasis.
FGFR inhibitors are promising tools that require further investigation to identify sensitive tumors. These studies suggest that targeting FGFR combined with other targeted therapies will be useful to impair breast cancer progression.
内分泌抵抗和转移扩散是乳腺癌治疗的主要临床挑战。成纤维细胞生长因子受体家族（FGFR）由四个酪氨酸激酶跨膜受体组成，参与关键的生物学过程。FGFR 的基因改变已在晚期乳腺癌中被确定，因此 FGFR 是一个有吸引力的治疗靶点。然而，FGFR 抑制剂对体内肿瘤生长的疗效仍存在争议。
本研究旨在评估 FGFR 在肿瘤生长和乳腺癌进展中的作用。
通过 3H-胸腺嘧啶摄取和细胞计数分别评估内分泌耐药性乳腺癌的原代培养物和人细胞系中的细胞增殖。肿瘤移植和细胞注射用于确定体内生长和自发转移。通过免疫组织化学评估原发性肿瘤中 FGFR1-3 和 αSMA 的表达。
抗孕激素耐药的鼠移植瘤和人异种移植瘤表达高水平的总 FGFR1-3。与载体相比，FGFR 抑制剂 BGJ398 处理体外耐药变体可抑制细胞增殖。在体内，与对照相比，BGJ398 治疗减少了四分之一个耐药肿瘤，但所有肿瘤均显示出上皮/基质比例降低。最后，在一种自发转移到肺部的激素耐药性乳腺癌模型中，BGJ398 减少了发生肺部转移的小鼠数量。
FGFR 抑制剂是很有前途的工具，需要进一步研究以确定敏感肿瘤。这些研究表明，靶向 FGFR 结合其他靶向治疗将有助于削弱乳腺癌的进展。
