ORAI channels and cancer

Cancer is a major cause of death. The diversity of cancer types and the propensity of cancers to acquire resistance to therapies, including new molecularly targeted and immune-based therapies, drives the search for new ways to understand cancer progression. The remodelling of calcium (Ca²⁺) signalling and the role of the Ca²⁺ signal in controlling key events in cancer cells such as proliferation, invasion and the acquisition of resistance to cell death pathways is well established. Most of the work defining such changes has focused on Ca²⁺ permeable Transient Receptor Potential (TRP) Channels and some voltage gated Ca²⁺ channels. However, the identification of ORAI channels, a little more than a decade ago, has added a new dimension to how a Ca²⁺ influx pathway can be remodelled in some cancers and also how calcium signalling could contribute to tumour progression. ORAI Ca²⁺ channels are now an exemplar for how changes in the expression of specific isoforms of a Ca²⁺ channel component can occur in cancer, and how such changes can vary between cancer types (e.g. breast cancer versus prostate cancer), and even subtypes (e.g. oestrogen receptor positive versus oestrogen receptor negative breast cancers). ORAI channels and store operated Ca²⁺ entry are also highlighting the diverse roles of Ca²⁺ influx pathways in events such as the growth and metastasis of cancers, the development of therapeutic resistance and the contribution of tumour microenvironmental factors in cancer progression. In this review we will highlight some of the studies that have provided evidence for the need to deepen our understanding of ORAI Ca²⁺ channels in cancer. Many of these studies have also suggested new ways on how we can exploit the role of ORAI channels in cancer relevant processes to develop or inform new therapeutic strategies.