The present invention provides, inter alia, methods, kits, and compositions for treating or ameliorating the effects of a cancer in a subject in need thereof. This method includes administering to the subject an effective amount of (i) a first anti-cancer agent, which is BVD-523 or a pharmaceutically acceptable salt thereof and (ii) a second anti-cancer agent, which is an inhibitor of the PI3K/Akt pathway or a pharmaceutically acceptable salt thereof. Also provided are methods of treating or ameliorating the effects of a subject with cancer in which the subject has a somatic KRAS and a somatic PIK3CA mutation or in which the cancer is refractory to a therapy selected from RAF inhibitor therapy, MEK inhibitor therapy, and RAF and MEK inhibitor therapy.
