MEK162 (ARRY-162, ARRY-438162) is a novel, selective inhibitor of MEK 1/2 with IC50 of about 12 nM [1].
Co-treatment of MEK162 and PKC inhibitors persistently inhibited MAP-kinase pathway. The co-treatment can halt proliferation and induce apoptosis of uveal melanoma cells even with GNAQ or GNA11 mutations [2]. All N-RAS mutant melanoma cells were sensitive to MEK 162. MEK162 reduced ERK1/2 phosphorylation, clonogenic survival, and induced apoptosis [3].
Phase Ib or II clinical trials were conducted in 32 cutaneous melanoma patients. 20 patients in MEK162 monotherapy and 12 on MEK162 plus RAF inhibitor or selective BRAF inhibitor combination therapy underwent ophthalmological examinations and multimodal imaging. These therapy all induced transient retinopathy with multiple bilateral lesions in some patients. The effect of MEK162 in retinopathy has been usually mild, self-limiting, and tolerable [4].
References:
[1]. Jed Pheneger, Eli Wallace, Allison Marlow, Brian Hurley, Joe Lyssikatos, Alison M. Bendele, Patrice A. Lee1. Array BioPharma, Boulder, CO; Bolder BioPath, Boulder, CO. Characterization of ARRY-438162, a potent MEK inhibitor in combination with Methotrexate or Ibuprofen in vivo models of arthritis. American college of rheumatology. 2006 Annual Scientific Meeting.
[2]. Chen X, Wu Q, Tan L, Porter D, Jager MJ, Emery C, Bastian BC. Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations. Oncogene. 2013 Oct 21.
[3]. Thumar J, Shahbazian D, Aziz SA, Jilaveanu LB, Kluger HM. MEK targeting in N-RAS mutated metastatic melanoma. Mol Cancer. 2014 Mar 4;13:45.
[4]. Urner-Bloch U, Urner M, Stieger P, Galliker N, Winterton N, Zubel A, Moutouh-de Parseval L, Dummer R, Goldinger SM. Transient MEK inhibitor-associated retinopathy in metastatic melanoma. Ann Oncol. 2014 May 26. pii: mdu169.