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

奥西替尼是阿斯利康开发的一种治疗非小细胞肺癌（NSCLC）的一线药物，用于抑制突变的上皮生长因子受体（EGFRm）。奥希替尼治疗的一个挑战是大量患者最终会产生耐药性。多组学方法被用来表征导致耐药状态的许多途径，并且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性的治疗方法。不幸的是，对奥希替尼的耐药性具有高度异质性，而且很大一部分复发患者具有未知的耐药驱动因素。众所周知，奥希替尼敏感细胞会抑制糖酵解，并且在药物存在的情况下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不同的敏感性。然而，人们对 EGFRm NSCLC 细胞的基础代谢变化知之甚少，因为它们进展到超出这些全局能量途径的耐药性。此外，已知导致复发患者产生耐药性的基因改变（例如 PIK3CA 突变）可以调节代谢途径。这就需要更好地了解癌细胞对奥希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.