Investigating multi-drug resistance in lung cancer using metabolomics and cell biology

奥西莫替尼是阿斯利康开发的治疗非小细胞肺癌(NSCLC)的一线药物，用于抑制突变的上皮生长因子受体(EGFRm)。奥西莫替尼治疗的一个挑战是在相当数量的患者中最终产生耐药性。一种多组学方法正在被用来描述导致耐药状态的一些途径，这些信息正在被转化到临床，在那里正在测试绕过获得性耐药的治疗方法。不幸的是，对奥西莫替尼的耐药性是高度异质性的，而且很大一部分复发患者的耐药性驱动因素不明。众所周知，奥西莫替尼敏感细胞抑制糖酵解，并在药物存在时增加对氧化磷酸化的依赖。相反，耐药细胞在药物治疗期间维持其糖酵解代谢，并对氧化磷酸化抑制剂具有不同的敏感性。然而，对于EGFRm NSCLC细胞在这些全球能量通路之外的耐药进展过程中基础代谢的变化知之甚少。此外，导致复发患者耐药的基因改变(如PIK3CA突变)已知可调节代谢途径。这就需要更好地了解当癌细胞对奥西莫替尼产生耐药性时发生的代谢变化。

Osimertinib is a 1st-line treatment for non-small cell lung cancer (NSCLC) developed by AstraZeneca to inhibit mutated epithelial growth factor receptor (EGFRm). A challenge with Osimertinib treatment is the eventual development of drug resistance in a significant number of patients. A multi-omic approach is being used to characterize a number of pathways leading to the resistant state, and this information is being translated to the clinic, where treatments bypassing the acquired drug resistance are being tested. Unfortunately, resistance to Osimertinib is highly heterogeneous, and moreover a significant proportion of relapsed patients have unknown drivers of resistance. It is known that Osimertinib-sensitive cells suppress glycolysis and have an increased dependence on oxidative phosphorylation in the presence of drug. Conversely, resistant cells maintain their glycolytic metabolism during drug treatment, and have variable sensitivities to oxidative phopshorylation inhibitors. However, little is known about changes to the basal metabolism of EGFRm NSCLC cells as they progress to resistance beyond these global energy pathways. Furthermore, genetic alterations that drive resistance in relapsed patients (e.g. PIK3CA mutation) are known to regulate metabolic pathways. This necessitates the better understanding of the metabolic changes occurring as cancer cells gain Osimertinib resistance.