Ribociclib enhances infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma.
Ribociclib enhances infigratinib-induced cancer cell differentiation and delays resistance in FGFR-driven hepatocellular carcinoma.
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DOI：
10.1111/liv.14728
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Huynh H
中科院分区：
文献类型：
--
作者：
Prawira A;Le TBU;Vu TC;Huynh H
Infigratinib是一种泛FGFR（成纤维细胞生长因子受体）抑制剂，在FGFR依赖性肝细胞癌（HCC）模型中显示出令人鼓舞的活性。然而，长期治疗会导致耐药菌落的出现。我们试图了解infigratinib诱导肿瘤细胞分化和耐药性背后的机制，并探索添加CDK 4/6抑制剂ribociclib延长细胞分化的潜力。将9个高表达FGFR 1 - 3和3个低表达FGFR 1 - 3的HCC患者来源的异种移植（PDX）肿瘤皮下植入SCID小鼠，随后单独使用infigratinib或与ribociclib联合治疗。然后对肿瘤组织进行免疫组化，以评估细胞分化，如细胞质/核比和标志物（如CYP 3A 4、HNF 4 α和白蛋白）所示。进行蛋白质印迹分析以研究所涉及的信号通路。在FGFR 1 - 3依赖性HCC PDX模型中，Infigratinib可诱导细胞分化，表现为细胞质/细胞核比增加以及CYP 3A 4、HNF 4 α和白蛋白增加。在长期治疗中出现耐药集落，其特征为分化细胞形态逆转、细胞质与细胞核比率降低和分化标志物丢失。Western印迹分析鉴定了CDK 4/Cdc 2/Rb通路的增加。添加ribociclib有效地阻断了这一途径并逆转了对infigratinib的耐药性，导致细胞分化和生长抑制延长。我们的研究结果表明，FGFR/CDK 4/6通路的联合抑制在提供持久的肿瘤生长抑制和细胞分化以及减少耐药性方面非常有效。因此，有必要在FGFR 1 - 3依赖性HCC患者中进行进一步的临床研究。
Infigratinib is a pan‐FGFR (fibroblast growth factor receptor) inhibitor that has shown encouraging activity in FGFR‐dependent hepatocellular carcinoma (HCC) models. However, long‐term treatment results in the emergence of resistant colonies. We sought to understand the mechanisms behind infigratinib‐induced tumour cell differentiation and resistance and to explore the potential of adding the CDK4/6 inhibitor ribociclib to prolong cell differentiation. Nine high and three low FGFR1‐3‐expressing HCC patient‐derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and subsequently treated with either infigratinib alone or in combination with ribociclib. Tumour tissues were then subjected to immunohistochemistry to assess cell differentiation, as indicated by the cytoplasmic‐to‐nuclear ratio and markers such as CYP3A4, HNF4α and albumin. Western blot analyses were performed to investigate the signalling pathways involved. Infigratinib induced cell differentiation in FGFR1‐3‐dependent HCC PDX models, as indicated by an increase in the cytoplasmic/nuclear ratio and an increase in CYP3A4, HNF4α and albumin. Resistant colonies emerged in long‐term treatment, characterised by a reversal of differentiated cell morphology, a reduction in the cytoplasmic‐to‐nuclear ratio and a loss of differentiation markers. Western blot analyses identified an increase in the CDK4/Cdc2/Rb pathway. The addition of ribociclib effectively blocked this pathway and reversed resistance to infigratinib, resulting in prolonged cell differentiation and growth inhibition. Our findings demonstrate that the combined inhibition of FGFR/CDK4/6 pathways is highly effective in providing long‐lasting tumour growth inhibition and cell differentiation and reducing drug resistance. Therefore, further clinical investigations in patients with FGFR1‐3‐dependant HCC are warranted.
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