Specific, targetable molecules mediating acquired resistance of B-RAF-mutant melanomas to a B-RAF inhibitor, thereby providing materials and methods for the treatment and detection of B-RAF inhibitor resistant cancers, such as melanoma. A method of identifying a patient to be treated with an alternative to B-RAF inhibitor therapy is described. Also described is a method of treating a patient having cancer. The patient is administered a MEK inhibitor, optionally in conjunction with vemurafenib therapy, or an inhibitor of the MAPK pathway (RAF, MEK, ERK) in conjunction with an inhibitor of the RTK-PI3K-AKT-mTOR pathway.
