Dual inhibition of BCL-XL and MCL-1 is required to induce tumour regression in lung squamous cell carcinomas sensitive to FGFR inhibition
Dual inhibition of BCL-XL and MCL-1 is required to induce tumour regression in lung squamous cell carcinomas sensitive to FGFR inhibition
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DOI：
10.1038/s41388-018-0268-2
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发表时间：
2018-08-09
期刊：
影响因子：
8
通讯作者：
Asselin-Labat, Marie-Liesse
中科院分区：
文献类型：
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作者：
Weeden, Clare E.;Ah-Cann, Casey;Asselin-Labat, Marie-Liesse
成纤维细胞生长因子受体(FGFRs)的遗传改变已在多种实体肿瘤中被描述，包括膀胱癌、头颈部和肺鳞状细胞癌(SqCC)。然而，最近的临床试验显示，FGFR靶向治疗肺部SqCC的疗效有限，提示联合治疗可能是必要的，以改善患者的预后。在这里，我们证明，FGFR治疗通过增加促凋亡蛋白BIM的表达来启动SqCC的细胞死亡。因此，我们假设，将支持生存蛋白的有效抑制剂BH3模拟物与FGFR靶向治疗相结合，可能会增强对SqCC细胞的杀伤。使用患者来源的异种移植和bcl2、bclxl和mcl1的特异性抑制剂，我们发现肺SqCC细胞对bclxl和mcl1的依赖程度高于bcl2。然而，在体内联合FGFR治疗中，bclxl和mcl1抑制剂单独使用都不能提供生存益处。BCL-XL、MCL-1和FGFR三重抑制可使肿瘤体积缩小，体内生存时间延长，说明BCL-XL和MCL-1蛋白在肺鳞癌中具有相互补偿的能力。因此，我们的工作为抑制MCL-1、BCL-XL和FGFR1以最大化表达FGFR1的肺SqCC的治疗反应提供了理论基础。
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.