Regulatory chromatin rewiring promotes metabolic switching during adaptation to oncogenic receptor tyrosine kinase inhibition.
Regulatory chromatin rewiring promotes metabolic switching during adaptation to oncogenic receptor tyrosine kinase inhibition.
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DOI：
10.1038/s41388-022-02465-w
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发表时间：
2022-10
期刊：
影响因子：
8
通讯作者：
Sharrocks, Andrew D.
中科院分区：
文献类型：
--
作者：
Ogden, Samuel;Carys, Kashmala;Ahmed, Ibrahim;Bruce, Jason;Sharrocks, Andrew D.
食管腺癌（OAC）患者的生存率很低，并且几乎没有靶向分子治疗。然而，OAC中受体酪氨酸激酶（RTK）驱动途径的组分通常发生突变，典型表现为RTK ERBB2的高频扩增。ERBB2可以作为治疗靶点，但由于获得耐药性，其临床获益有限。在这里，我们研究了OAC细胞如何适应ERBB2抑制，因为它们过渡到耐药状态。ERBB2抑制触发可接近的染色质景观和潜在的基因调控网络的广泛重塑。转录调节因子HNF4A和PPARGC 1A在这个网络重新布线中起着关键作用。最初，观察到细胞周期相关基因表达程序的抑制，程序的补偿性增加驱动代谢活性的变化。PPARGC 1A和HNF 4A都是获得对ERBB 2抑制的抗性所必需的，PPARGC 1A有助于促进对氧化磷酸化的依赖性的转变。因此，我们的工作揭示了支持获得耐药状态的分子途径，并指出了潜在的新治疗策略，以对抗细胞适应和随之而来的耐药性。
Oesophageal adenocarcinoma (OAC) patients show poor survival rates and there are few targeted molecular therapies available. However, components of the receptor tyrosine kinase (RTK) driven pathways are commonly mutated in OAC, typified by high frequency amplifications of the RTK ERBB2. ERBB2 can be therapeutically targeted, but this has limited clinical benefit due to the acquisition of drug resistance. Here we examined how OAC cells adapt to ERBB2 inhibition as they transition to a drug resistant state. ERBB2 inhibition triggers widespread remodelling of the accessible chromatin landscape and the underlying gene regulatory networks. The transcriptional regulators HNF4A and PPARGC1A play a key role in this network rewiring. Initially, inhibition of cell cycle associated gene expression programmes is observed, with compensatory increases in the programmes driving changes in metabolic activity. Both PPARGC1A and HNF4A are required for the acquisition of resistance to ERBB2 inhibition and PPARGC1A is instrumental in promoting a switch to dependency on oxidative phosphorylation. Our work therefore reveals the molecular pathways that support the acquisition of a resistant state and points to potential new therapeutic strategies to combat cellular adaptation and ensuing drug resistance.
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影响因子：
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作者：
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通讯作者：
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