Editors' ChoiceCancer

Active but not oncogenic

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Science Signaling  18 Aug 2015:
Vol. 8, Issue 390, pp. ec232
DOI: 10.1126/scisignal.aad2461

The mitogen-activated protein kinase (MAPK) pathway RAF-MEK-ERK mediates a wide range of signals from growth to death and is implicated in many malignancies. Herrero et al. (see commentary by Karra et al.) investigated the effects on ERK signaling and ERK-mediated cellular responses of a water-soluble, 3-arylidene-2-oxindole derivative compound (DEL-22379). DEL-22379 prevented ERK dimerization induced by epidermal growth factor (EGF) in HEK293 cells; however, the amount of EGF-induced ERK phosphorylation, which typically correlates with activity, was unaffected by DEL-22379. The inhibition of ERK dimerization by DEL-22379 was confirmed in proximity ligation assays performed in HeLa cells stimulated with EGF. In silico docking studies indicated that DEL-22379 bound to ERK2 at a groove within the dimerization interface. HEK293 cells exposed to DEL-22379 and stimulated with EGF showed reduced phosphorylation of the ERK cytoplasmic substrate, RSK1, but increased phosphorylation of the ERK nuclear substrates ELK, FOS, and MYC, suggesting that prevention of dimerization reduced ERK cytoplasmic signaling and increased nuclear signaling. DEL-22379 reduced growth of different cancer cell lines harboring mutant BRAF (V600E) or mutant RAS more effectively than did the inhibitor SCH-772984, which inhibits the kinase activity of ERK, or than did the inhibitor PD-0325901, which inhibits the kinase activity of MEK. DEL-22379 treatment also showed increased apoptosis in these cells. Intraperitoneal injection of DEL-22379 into nude mice xenografted with cells, such as A375 with a mutation in BRAF and HCT116 with a mutation in KRAS, resulted in reduced cancer progression. Treatment of mice xenografted with patient-derived colorectal adenocarcinoma cells with DEL-22379 retarded tumor progression by increasing cell death. Thus this study indicated that chemical inhibition of ERK dimerization may limit cancer progression without reducing ERK phosphorylation or abundance, which could reduce the potential side effects of ERK-targeted or ERK pathway-targeted therapeutics.

A. Herrero, A. Pinto, P. Colón-Bolea, B. Casar, M. Jones, L. Agudo-Ibáñez, R. Vidal, S. P. Tenbaum, P. Nuciforo, E. M. Valdizán, Z. Horvath , L. Orfi, A. Pineda-Lucena, E. Bony, G. Keri, G. Rivas, A. Pazos, R. Gozalbes, H. G. Palmer, A. Hurlstone, P. Crespo, Small molecule inhibition of ERK dimerization prevents tumorigenesis by RAS-ERK pathway oncogenes. Cancer Cell 28, 170–182 (2015). [PubMed]

A. S. Karra, C. A. Taylor IV, C. A. Thorne, M. H. Cobb, A kinase divided. Cancer Cell 28, 145–147 (2015). [PubMed]