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

奥希替尼是阿斯利康开发的用于抑制突变的上皮生长因子受体（EGFRm）的非小细胞肺癌（NSCLC）一线治疗药物。奥希替尼治疗的一个挑战是在大量患者中最终产生耐药性。一种多组学方法正在被用于表征导致耐药状态的许多途径，这些信息正在被转化为临床，其中正在测试绕过获得性耐药性的治疗方法。不幸的是，对奥希替尼的耐药性是高度异质性的，而且相当大比例的复发患者具有未知的耐药性驱动因素。已知存在药物时，奥希替尼敏感细胞抑制糖酵解，并对氧化磷酸化的依赖性增加。相反，耐药细胞在药物治疗期间维持其糖酵解代谢，并且对氧化磷酸化抑制剂具有可变的敏感性。然而，关于EGFRm NSCLC细胞的基础代谢的变化知之甚少，因为它们在这些全局能量途径之外进展为耐药性。此外，已知在复发患者中驱动抗性的遗传改变（例如PIK3CA突变）调节代谢途径。这需要更好地了解癌细胞获得奥希替尼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.