Searching for the Chokehold of NRAS Mutant Melanoma

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Searching for the Chokehold of NRAS Mutant Melanoma Christian Posch, Igor Vujic, Babak Monshi, Martina Sanlorenzo, Felix Weihsengruber, Klemens Rappersberger, Susana Ortiz-Urda Journal of Investigative Dermatology Volume 136, Issue 7, Pages 1330-1336 (July 2016) DOI: 10.1016/j.jid.2016.03.006 Copyright © 2016 The Authors Terms and Conditions

Figure 1 Conceptual schema of NRAS cycling and mutation hotspots. (a) Wild-type NRAS cycles between an inactive GDP bound and an active GTP bound state. Upstream signals trigger the activation of NRAS which is regulated by GEFs (such as SOS1). NRAS deactivation is catalyzed by GAPs (such as NF1). (b) NRAS mutations are located at codon 12/13, affecting the P-loop (Walker A motif) of the protein. Mutations at codon 61 impair the intrinsic catalytic activity of NRAS located in the switch II domain of the protein. (c) Mutant NRAS impairs normal protein cycling, locking the protein in its active GTP bound state. GAP, GTPase activating protein; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factors; GTP, guanosine triphosphate; HVR, hypervariable region; NRAS, neuroblastoma rat-sarcoma homolog; RTK, receptor tyrosine kinases; SWI/II, switch I/II. Journal of Investigative Dermatology 2016 136, 1330-1336DOI: (10.1016/j.jid.2016.03.006) Copyright © 2016 The Authors Terms and Conditions

Figure 2 Conceptual schema highlighting some of the most studied pathways involved in signaling of NRAS mutant melanoma. Horizontal inhibition refers to targeting of signaling members within different pathways, such as combinations of MEK/AKT, MEK/PI3K, MEK/CDK4, and MEK/Plk1. Vertical inhibition refers to targeting of signaling members within one pathway. This approach is currently investigated by combinatorial targeting of MEK/ERK in the MAPK pathway. MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; NRAS, neuroblastoma rat-sarcoma homolog. Journal of Investigative Dermatology 2016 136, 1330-1336DOI: (10.1016/j.jid.2016.03.006) Copyright © 2016 The Authors Terms and Conditions