Abstract 2437: MEK162 (ARRY 438162), a MEK1/2 inhibitor, has activity in melanoma cells independent of BRAF and NRAS mutation status.
Authors: Von Euw Erika M. , Rong Hong-Mei , O'Brien Neil , Conklin Dylan , Konkankit Veerauo , Gong Ke-Wei , Zubel Angela , Linnartz Ronald , Finn Richard , Chmielowski Bartosz , Slamon Dennis 
Published: August 2014

Background. Activation of the Ras/Raf/MEK/MAP kinase pathway is implicated in uncontrolled cell proliferation and tumor growth. Mutated, oncogenic forms of Ras are found in colon, pancreatic, and lung cancers; BRAF mutations have been identified in more than 60% of malignant melanomas and from 40-60% of papillary thyroid cancers. MEK, a dual specific kinase, is a key player in this pathway; it is downstream of both Ras and Raf and activates ERK1/2 through phosphorylation of key tyrosine and threonine residues. MEK162 (ARRY 438162) is a novel small molecule ATP-uncompetitive inhibitor of the kinases MEK1 and MEK2. MEK162 showed promising data in an ongoing Phase 2 Clinical Trial in patients with BRAF and NRAS mutated advanced melanoma. This is the first targeted therapy to show activity in patients with NRAS mutated melanoma. Methods and Results. The melanoma cell line panel was the most sensitive after investigating the growth inhibitory effect of MEK162 on 328 cancer cell lines from diverse histologies including melanoma, head and neck, colon, pancreas, lung, ovarian, liver, kidney, breast and endometrial. When a cutoff of IC50 &lt;500nM or &gt;70% Inhibition at 1uM after 6 days of culture was used 83% out of 47 melanoma cell lines were sensitive to the treatment with the MEK inhibitor. Sensitivity to MEK162 was independent of BRAFV600E andNRASQ61mutation status in this cell line panel. Cell cycle arrest and apoptosis was assessed upon exposure to MEK162 using flow cytometry. MEK162 led to a G1 arrest and marked increase in apoptotic cells in the majority of the sensitive melanoma cell lines regardless of their origin and oncogenic driver mutations. Western blots were used to characterize the changes induced by exposure to MEK162 in the MAPK and PI3K/mTOR pathways. MEK1/2 inhibition resulted in a decrease in pERK in all the cell lines tested regardless of their mutational status and the in vitro sensitivity. We observed an increase in pMEK more prominently in NRASQ61L mutant and wild type for NRAS and BRAF mutations cell lines than in BRAFV600Emutant cell lines. We found pAKT and pS6 decreased in the NRAS and BRAF mutant cell lines after treatment, suggesting that the inhibition of the mTOR pathway by MEK162 may be crucial for the sensitivity to the drug. Conclusion. These data provide evidence for supporting the use of MEK162 in the treatment of patients with melanoma.

Citation Format: Erika M. Von Euw, Hong-Mei Rong, Neil O'Brien, Dylan Conklin, Veerauo Konkankit, Ke-Wei Gong, Angela Zubel, Ronald Linnartz, Richard Finn, Bartosz Chmielowski, Dennis Slamon. MEK162 (ARRY 438162), a MEK1/2 inhibitor, has activity in melanoma cells independent of BRAF and NRAS mutation status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2437. doi:10.1158/1538-7445.AM2013-2437