Anoctamins and Calcium Signalling: An Obstacle to EGFR Targeted Therapy in Glioblastoma?

SIMPLE SUMMARY: Glioblastoma is the most lethal form of brain cancer in adults. No new successful treatments have been developed in 30 years and survival rates have not improved, primarily because of a lack of effective drug treatments. Up to 60% of glioblastoma tumours have increased activity of a growth factor called epidermal growth factor receptor, which drives tumour growth. However, targeted therapies against the epidermal growth factor receptor have failed in clinical trials. A key reason for this is cell plasticity, a trait of brain cells that allow them to change their function in response to their environment. Tumour cells use plasticity to evade anti-cancer drugs. A group of genes called anoctamins may be involved in promoting tumour cell plasticity, which are believed to regulate cancer cell behaviour. This review summarises how anoctamins may regulate growth factor signalling and discusses a novel theory on how anoctamins may contribute to treatment resistance in glioblastoma. ABSTRACT: Glioblastoma is the most common form of high-grade glioma in adults and has a poor survival rate with very limited treatment options. There have been no significant advancements in glioblastoma treatment in over 30 years. Epidermal growth factor receptor is upregulated in most glioblastoma tumours and, therefore, has been a drug target in recent targeted therapy clinical trials. However, while many inhibitors and antibodies for epidermal growth factor receptor have demonstrated promising anti-tumour effects in preclinical models, they have failed to improve outcomes for glioblastoma patients in clinical trials. This is likely due to the highly plastic nature of glioblastoma tumours, which results in therapeutic resistance. Ion channels are instrumental in the development of many cancers and may regulate cellular plasticity in glioblastoma. This review will explore the potential involvement of a class of calcium-activated chloride channels called anoctamins in brain cancer. We will also discuss the integrated role of calcium channels and anoctamins in regulating calcium-mediated signalling pathways, such as epidermal growth factor signalling, to promote brain cancer cell growth and migration.