CDK4 and melanoma: Of note, however, combined CDK4/6 and MAP kinase inhibition is also complicated by resistance, and in the case of melanomas, related to pS6 expression via PI3K pathway activation [47, 48], so that mTOR inhibition may be germane to reversing resistance to CDK4/6 inhibitor monotherapy, as well as combined CDK4/6 and MAP kinase inhibition.