Loss of the PTEN tumor suppressor, which activates the PI3K-AKT pathway, was initially discovered as a highly recurrent event in primary brain tumors (GBMs).14 Interestingly, there is now growing data implicating activation of the PI3K-AKT pathway in brain metastases from melanoma and other tumor types.49 Multiple studies have identified increased activation of the PI3K-AKT pathway in MBMs, including in comparison to extracranial metastases from the same patients.16,50 It appears that this molecular phenotype could be caused by multiple mechanisms. Here, PIK3CA is linked to melanoma.