The most advanced treatment options for metastatic colorectal cancer (mCRC) patients are antibodies that bind to and inhibit the activity of the epidermal growth factor receptor (EGFR). EGFR is a key regulator of pro-survival signalling pathways, with deregulation central to CRC tumour initiation and progression. Given the complexity of downstream signalling pathways, targeting a single component may not always be effective. With five-year survival rates for metastatic colorectal cancer remaining less than 20%, new avenues of therapeutic intervention are urgently needed.
In recent years, the anti-diabetic drug metformin has been shown to exert potentially important anti-cancer effects in patients with Type 2 diabetes. Whether these anti-cancer properties can be harnessed in different cancer settings for non-diabetic patients is currently the subject of intense study. Metformin exerts its effects by activating AMP protein kinase (AMPK), a sensor of energy stress in a cell. Intriguingly, this sensor has been shown to block signalling downstream of the EGFR receptor in order to conserve energy use within a cell.
In an effort to identify a subset of patients that may benefit from metformin treatment, either singly, or in conjunction with anti-EGFR therapeutics, we have assessed the efficacy of metformin treatment in a large panel of CRC cell lines. Gene expression signatures of sensitive and resistant cell lines have been compared and stratified, both at a basal level and in response to metformin treatment. We have also explored a panel of isogenic CRC cell lines to determine whether mutations in KRAS or BRAF affect susceptibility to metformin treatment, as has previously been shown in other cancer settings. Initial findings of these investigations will be presented.