Resistance mutations and the blood–brain barrier: Key challenges in targeted treatment of brain metastatic non-small cell lung cancer

Abstract

Over the past two decades, marked progress has been made in treating non-small cell lung cancer (NSCLC) patients with EGFR-, ALK-, ROS1- and KRAS^G12C-targeted inhibitors. NSCLC patients very often develop brain metastases. Despite the continuous development of newer and better inhibitors, the survival outcomes of NSCLC patients with brain metastases remain significantly worse than those of patients without. The main challenges in these pharmacotherapies are the development of resistance mutations, and, potentially, the presence of the blood–brain barrier (BBB). The outcomes of clinical studies show the improved efficacy of later-generation targeted inhibitors. The increase in progression free survival (PFS) in patients treated with these later-generation inhibitors is largely attributed to their efficacy against multiple resistance mutations, and possibly due to enhanced brain penetration. This review explores the different aspects hindering the targeted treatment of NSCLC and especially of brain metastases, focusing on recent clinical trials and emerging resistance mutations and the influence of the BBB on the efficacy of EGFR, ALK, ROS1 and KRAS^G12C inhibitors. The role of the ABCB1 and ABCG2 drug transporters in differential efflux of the targeted drugs at the BBB is also discussed, since preclinical studies indicate that they may reduce the efficacy of transported inhibitors.