Antitumor Activity of the Selective Pan-RAF Inhibitor TAK-632 in BRAF Inhibitor-Resistant Melanoma

摘要: The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of melanoma cells. Somatic mutations in BRAF NRAS are frequently observed melanoma. Recently, inhibitors vemurafenib dabrafenib have emerged as promising agents treatment patients with BRAF-activating mutations. However, induce RAF paradoxical activation via dimerization wild-type cells, rapid emergence acquired resistance secondary skin tumors well presence few effective options bearing (including NRAS-mutant melanoma) clinical concerns. Here, we demonstrate that selective pan-RAF inhibitor TAK-632 suppresses activity cells minimal activation. Our analysis using RNAi preclinical models reveals MAPK NRAS-mutated highly dependent on RAF. We also show induces but inhibits dimer, probably because its slow dissociation from As a result, demonstrates potent antiproliferative effects both BRAF-mutated to through mutation or truncation. Furthermore, combination (MEK) TAK-733 exhibits synergistic these findings characterize unique features provide rationale further investigation subset melanomas refractory inhibitors.