Reactome | Dual mechanism MAP2K inhibitors bind MAP2Ks

Dual mechanism MAP2K inhibitors bind MAP2Ks

Stable Identifier

R-HSA-9657599

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, cytosol

ReviewStatus

5/5

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Dual mechanism MAP2K inhibitors bind MAP2Ks

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Although mutations in MAP2K proteins are infrequent in human cancers, the position of these kinases downstream of RAS and RAF make them good candidates for therapeutic targeting. Dual mechanism inhibitors such as trametinib bind to non-phosphorylated MAP2K proteins, inhibiting their MAPK-directed kinase activity as well as preventing their phosphorylation by RAF proteins (Hatzivassiliou et al, 2013; Lito et al, 2014; Ishii et al, 2013; reviewed in Samatar and Poulikakos, 2014).

Literature References

PubMed ID	Title	Journal	Year
24746704	Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors Lukacs, C, Morikami, K, Solomon, M, Gadal, S, Lowe, S, Ohara, K, Miura, T, Joseph, E, Fellmann, C, Lito, P, Saborowski, M, Kastenhuber, E, Rosen, N, Ishii, N, Saborowski, A, Yue, J	Cancer Cell	2014
23667175	Enhanced inhibition of ERK signaling by a novel allosteric MEK inhibitor, CH5126766, that suppresses feedback reactivation of RAF activity Sakai, T, Shimma, N, Tomii, Y, Sowa, Y, Tachibana-Kondo, Y, Aoki, T, Poulikakos, PI, Matsuda, Y, Joseph, EW, Sakamoto, H, Aoki, Y, Iikura, H, Arisawa, M, Harada, N, Ohara, K, Miura, T, Rosen, N, Ishii, N	Cancer Res.	2013
23934108	Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers Merchant, M, Haling, JR, Luoh, SM, Wiesmann, C, Price, S, Heald, R, Ultsch, M, Hatzivassiliou, G, Belvin, M, Peck, A, Ludlam, MJ, Zak, M, Hewitt, JF, Malek, S, Chan, J, Orr, C, Friedman, LS, Anderson, DJ, Hoeflich, KP, Song, K, Chen, H	Nature	2013
25435214	Targeting RAS-ERK signalling in cancer: promises and challenges Poulikakos, PI, Samatar, AA	Nat Rev Drug Discov	2014