Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Despite decades of clinical trials, the overall survival rate for patients with relapsed and metastatic disease remains below 30%, underscoring the need for novel treatments. FGFR4, a receptor tyrosine kinase that is overexpressed in RMS and mutationally activated in 10% of cases, is a promising target for treatment. Here, we show that futibatinib, an irreversible pan-FGFR inhibitor, inhibits the growth of RMS cell lines in vitro by inhibiting phosphorylation of FGFR4 and its downstream targets. Moreover, we provide evidence that the combination of futibatinib with currently used chemotherapies such as irinotecan and vincristine has a synergistic effect against RMS in vitro. However, in RMS xenograft models, futibatinib monotherapy and combination treatment have limited efficacy in delaying tumor growth and prolonging survival. Moreover, limited efficacy is only observed in a PAX3-FOXO1 fusion-negative (FN) RMS cell line with mutationally activated FGFR4, whereas little or no efficacy is observed in PAX3-FOXO1 fusion-positive (FP) RMS cell lines with FGFR4 overexpression. Alternative treatment modalities such as combining futibatinib with other kinase inhibitors or targeting FGFR4 with CAR T cells or antibody-drug conjugate may be more effective than the approaches tested in this study.
横纹肌肉瘤（RMS）是最常见的儿童软组织肉瘤。尽管经过数十年的临床试验，复发和转移性患者的总体生存率仍低于30%，这凸显了对新型治疗方法的迫切需求。FGFR4是一种受体酪氨酸激酶，在RMS中过度表达且在10%的病例中发生突变激活，是一个有前景的治疗靶点。本研究显示，不可逆的泛FGFR抑制剂福替巴替尼通过抑制FGFR4及其下游靶点的磷酸化，在体外抑制RMS细胞系的生长。此外，我们提供证据表明，福替巴替尼与目前使用的化疗药物（如伊立替康和长春新碱）联合应用，在体外对RMS具有协同作用。然而，在RMS异种移植模型中，福替巴替尼单药治疗和联合治疗在延缓肿瘤生长和延长生存期方面效果有限。而且，仅在具有突变激活FGFR4的PAX3-FOXO1融合阴性（FN）RMS细胞系中观察到有限疗效，而在FGFR4过度表达的PAX3-FOXO1融合阳性（FP）RMS细胞系中则几乎无效果。其他治疗方式，如将福替巴替尼与其他激酶抑制剂联用，或采用CAR T细胞或抗体-药物偶联物靶向FGFR4，可能比本研究测试的方法更为有效。
Preclinical Evaluation of the FGFR-Family Inhibitor Futibatinib for Pediatric Rhabdomyosarcoma
肿瘤(癌症)患者之家