Abstract C138: Loss of NF1 in melanoma cell lines is associated with active Ras and dependence on MEK even in the absence of BRAF or NRAS mutation.

Abstract

Abstract Though two-thirds of cutaneous melanomas harbor activating mutations in the BRAF and NRAS genes, the alterations that drive tumor progression in the roughly 30% of melanoma tumors wild-type for BRAF and NRAS remain largely uncharacterized. The selective RAF inhibitors vemurafenib and dabrafenib inhibit MAPK pathway activity only in BRAF mutant cells, thus their clinical utility is restricted to patients with BRAF mutant tumors. MEK inhibitors, which have broader antitumor activity and have shown promising activity in NRAS mutant melanoma, may be effective in a broader range of MAPK pathway-dependent tumors. We performed a functional and genomic analysis of melanoma cell lines wild-type for BRAF and NRAS to determine whether occult mutations in RAS signaling were present. Elevated RAS-GTP was common in BRAF/NRAS wild-type melanoma cell lines, a subset of which exhibited total loss of NF1 protein expression. The proliferation of NF1-null melanoma cells was dependent upon MEK, though the cellular potency of several allosteric MEK inhibitors that are currently in clinical testing (PD0325901, AZD6244, MEK162 and trametinib) varied widely in NF1-null melanoma cells. The greatest antitumor activity was noted with trametinib, a MEK inhibitor that also blocks RAF mediated phosphorylation of MEK. Notably, alterations in NF1 also co-occurred with RAS and BRAF mutations in both cell lines and human melanomas. In the setting of BRAF co-mutation, loss of NF1 abrogated upstream negative feedback on RAS activation resulting in constitutive expression of RAS-GTP and resistance to RAF but not MEK inhibition. In summary, NF1 loss is a common event in cutaneous melanoma that is associated with RAS activation, MEK dependence and RAF inhibitor resistance. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C138. Citation Format: Moriah H. Nissan, Christine Pratilas, Alexis Jones, Helen Won, Li Kong, Zhan Yao, Taha Merghoub, Antoni Ribas, Paul Chapman, Rona Yaeger, Barry Taylor, Nikolaus Shultz, Michael F. Berger, Neal Rosen, David B. Solit. Loss of NF1 in melanoma cell lines is associated with active Ras and dependence on MEK even in the absence of BRAF or NRAS mutation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C138.