School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
Oncogene. 2022 Oct;41(43):4808-4822. doi: 10.1038/s41388-022-02465-w. Epub 2022 Sep 24.
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.
食管腺癌 (OAC) 患者的生存率较低，可用的靶向分子治疗方法也很少。然而，OAC 中常见受体酪氨酸激酶 (RTK) 驱动途径的成分发生突变，以 RTK ERBB2 的高频扩增为特征。可以对 ERBB2 进行治疗性靶向治疗，但由于获得耐药性，其临床获益有限。在这里，我们研究了 OAC 细胞在向耐药状态转变时如何适应 ERBB2 抑制。ERBB2 抑制会触发可及染色质景观和潜在基因调控网络的广泛重塑。转录调节因子 HNF4A 和 PPARGC1A 在这个网络重布线中起着关键作用。最初，观察到与细胞周期相关基因表达程序的抑制，伴随着代谢活性变化驱动程序的代偿性增加。PPARGC1A 和 HNF4A 对于获得 ERBB2 抑制的耐药性都是必需的，并且 PPARGC1A 对于促进对氧化磷酸化的依赖性转换至关重要。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，以对抗细胞适应性和随之而来的耐药性。
