Preclinical study on melanoma discovered that dual targeting of CDK4/6 and mutated BRAF or MEK resulted in BRAF and NRAS mutated melanoma.[30] Meanwhile, a study found that up-regulation or mutation of NRAS was related to the CDK4/6i resistance both in vivo model and clinical case, respectively.[3] Mutated BRAF and NRAS melanomas acquired resistance to inhibition of CDK4/6 by upregulating mTOR signaling.[49]. The gene discussed is NRAS; the disease is melanoma.