Resistance of Brain Tumours to Small-Molecule-Targeted Therapies: Lessons from Various Cancer Types

Abstract

Brain tumours are a heterogeneous group of central nervous system (CNS) neoplasms. The current treatment regime for brain tumours consists of surgical resection or sequential or concurrent chemoradiotherapy with chemotherapy such as temozolomide. Despite improvements in these treatments, survival rate is less than 10 % 5 years after diagnosis, and there are limited second-line treatments available. Although recent improvements in understanding the genomics of brain tumours such as glioblastomas (GBMs) have implicated several pathways, clinical success of targeted therapies has been limited. This is due in part to resistance (both intrinsic and acquired) to the therapies but also in part due to the intratumoural heterogeneity, limited vasculature, lack of CNS penetration and the blood-brain barrier limiting the efficacy of the agent. The use of targeted therapies has come to the forefront of oncology in the past decade. Monoclonal antibodies and small-molecule-targeted therapies such as tyrosine kinase inhibitors are currently being used for the treatment of a number of receptor and pathway alteration-driven forms of cancer. Resistance to targeted therapies has been the Achilles heel of the successful application of these emerging agents. By investigating the response to these therapies in many cancer types and examining any mechanisms of resistance, they may be utilised in the treatment of brain tumours.