Third, in two HER2-positive breast and colorectal PDX models harboring activating HER2 mutations (V777L and R678Q) derived from patients who had been treated with HER2-targeted therapies, the combination of neratinib with the MEK inhibitor trametinib, the mTOR inhibitors everolimus or sapanisertib, or the CDK4/6 inhibitor palbociclib synergistically decreased tumor volume to a greater extent than any of the agents alone. Here, MTOR is linked to neoplasm.