However, recent preclinical studies have revealed that tumour cells in GBM and other cancers may circumvent PI3K inhibition by inducing insulin feedback as a resistance mechanism to reactivate PI3K-mTOR signalling, suggesting that PI3K inhibitors may need to be coupled with anti-hyperglycemic therapies such as metformin to increase treatment efficacy [104, 105]. This evidence concerns the gene PIK3CA and glioblastoma.