Genetic alterations in the fibroblast growth factor receptors (FGFRs) have been described in multiple solid tumours including bladder cancer, head and neck and lung squamous cell carcinoma (SqCC). However, recent clinical trials showed limited efficacy of FGFR-targeted therapy in lung SqCC, suggesting combination therapy may be necessary to improve patient outcomes. Here we demonstrate that FGFR therapy primes SqCC for cell death by increasing the expression of the pro-apoptotic protein BIM. We therefore hypothesised that combining BH3-mimetics, potent inhibitors of pro-survival proteins, with FGFR-targeted therapy may enhance the killing of SqCC cells. Using patient-derived xenografts and specific inhibitors of BCL-2, BCL-XL, and MCL-1, we identified a greater reliance of lung SqCC cells on BCL-XL and MCL-1 compared to BCL-2 for survival. However, neither BCL-XL nor MCL-1 inhibitors alone provided a survival benefit in combination FGFR therapy in vivo. Only triple BCL-XL, MCL-1, and FGFR inhibition resulted in tumour volume regression and prolonged survival in vivo, demonstrating the ability of BCL-XL and MCL-1 proteins to compensate for each other in lung SqCC. Our work therefore provides a rationale for the inhibition of MCL-1, BCL-XL, and FGFR1 to maximize therapeutic response in FGFR1-expressing lung SqCC.

中文翻译：

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在对FGFR抑制敏感的肺鳞状细胞癌中诱导肿瘤消退需要BCL-XL和MCL-1的双重抑制。

已经在包括膀胱癌，头颈部和肺鳞状细胞癌（SqCC）在内的多种实体瘤中描述了成纤维细胞生长因子受体（FGFR）的遗传改变。但是，最近的临床试验表明，针对FGFR的疗法在肺SqCC中的疗效有限，这表明可能需要采用联合疗法来改善患者的预后。在这里，我们证明FGFR治疗可通过增加促凋亡蛋白BIM的表达来引发SqCC细胞死亡。因此，我们假设，将BH3模拟物（促存活蛋白的有效抑制剂）与FGFR靶向疗法结合使用，可能会增强SqCC细胞的杀伤力。使用患者来源的异种移植物和BCL-2，BCL-XL和MCL-1的特异性抑制剂，我们发现肺SqCC细胞对BCL-XL和MCL-1的依赖程度要高于BCL-2。然而，单独的BCL-XL抑制剂和MCL-1抑制剂都不能在体内联合FGFR治疗中提供生存益处。只有三倍的BCL-XL，MCL-1和FGFR抑制作用会导致肿瘤体积消退并延长体内存活时间，这表明BCL-XL和MCL-1蛋白在肺SqCC中相互补偿的能力。因此，我们的工作为抑制MCL-1，BCL-XL和FGFR1提供了理论依据，以最大程度地提高表达FGFR1的肺SqCC的治疗反应。