Abstract 4247: Characterization of the selective pan-RAF inhibitor TAK-632 with antitumor activity in BRAF inhibitor-resistant melanoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Melanoma is one of the deadliest and most aggressive forms of skin cancer, arising from the malignant transformation of pigment-producing cells, melanocytes. The mitogen-activated protein kinase (MAPK) pathway is particularly important for the survival and proliferation of melanoma cells and somatic mutations in BRAF and NRAS are frequently observed in melanoma. Recently, it has been reported that the BRAF inhibitors vemurafenib and dabrafenib showed high response rates and improved overall survival in melanomas with BRAF-activating mutations. However, as BRAF inhibitors induce RAF paradoxical activation via RAF dimerization in BRAF wild-type cells, rapid emergence of acquired resistance and secondary skin tumors as well as presence of few effective treatment options for melanoma bearing wild-type BRAF (including NRAS mutant melanoma) are clinical concerns. In this preclinical study, we describe the biological characterization of TAK-632 as a potent and selective pan-RAF inhibitor that suppresses RAF activity in BRAF wild-type cells with minimal RAF paradoxical activation. We used both genetic and chemical approaches to investigate the dependence of NRAS-mutated melanoma and BRAF inhibitor-resistant BRAF mutant melanoma cells on RAF. Our analysis reveals that the MAPK pathway and proliferation of these cells is highly dependent on RAF. Such dependence was not observed in several RAS/RAF-wild type and KRAS-mutated cells. We also show that TAK-632 induces RAF dimerization but inhibits the kinase activity of the RAF dimer, probably because of its slow dissociation from RAF. Furthermore, we demonstrate that the combination of TAK-632 and various MAPK kinase (MEK) inhibitors exhibits synergistic anti-proliferative effects on these cells. Our findings indicate that TAK-632 has favorable characteristics in terms of suppressing the proliferation of NRAS mutant melanoma and BRAF inhibitor-resistant BRAF mutant melanoma cells. Citation Format: Akito Nakamura, Takeo Arita, Shuntarou Tsuchiya, Jill Donelan, Jouhara Chouitar, Elizabeth Carideo, Katherine Galvin, Masanori Okaniwa, Tomoyasu Ishikawa, Sei Yoshida. Characterization of the selective pan-RAF inhibitor TAK-632 with antitumor activity in BRAF inhibitor-resistant melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4247. doi:10.1158/1538-7445.AM2014-4247