Alternatively, studies of MBMs have identified that these tumors harbor increased activation of the PI3K-AKT pathway and OXPHOS, both of which have previously been shown to cause resistance to BRAF and MEK inhibitors.14,61,62 Preclinical studies with PI3K-AKT pathway inhibitors, including in MBM models, suggest that they may have positive anti-tumor effects in combination with BRAF and MEK inhibitors,16,55 but this has yet to be evaluated in patients with brain metastases. This evidence concerns the gene BRAF and neoplasm.