Small-molecule blockade of ERK dimerization delays tumorigenesis driven by oncogenic RAS–ERK signaling.

  • Major finding: Small-molecule blockade of ERK dimerization delays tumorigenesis driven by oncogenic RAS–ERK signaling.

  • Mechanism: DEL-22379 inhibits ERK extranuclear activity and is not affected by drug-resistance mechanisms.

  • Impact: Regulatory protein–protein interactions represent potential therapeutic targets.

Constitutive activation of the RAS–ERK pathway occurs in nearly 50% of human cancers. Although several pharmacologic strategies to block this pathway have yielded positive results, long-lasting efficacy has been hampered by acquired resistance mutations that reactivate ERK signaling. As an alternative approach, Herrero and colleagues sought to inhibit ERK dimerization, which specifically regulates the extranuclear function of ERK and has been implicated in tumorigenesis. Screening of small-molecule libraries identified DEL-22379, which successfully blocked ERK dimerization without affecting its phosphorylation; correspondingly, ERK cytoplasmic activity was significantly reduced, whereas its nuclear functions were enhanced. Mutation of residues within the dimerization interface of ERK disrupted the effects of DEL-22379, indicating that the compound binds directly to this interface and blocks dimer formation. DEL-22379 inhibited growth and induced apoptosis in various tumor cell lines harboring mutant BRAF or RAS, whereas wild-type cell lines were resistant. In vivo, DEL-22379 selectively inhibited the growth and metastasis of BRAF-mutant cell line–derived and patient-derived xenografts. Expression of phosphoprotein enriched in astrocytes 15 (PEA15), which retains ERK in the cytoplasm, correlated with levels of ERK dimerization and DEL-22379 sensitivity in BRAF-mutant cells, supporting the idea that the antitumor activity of DEL-22379 is dependent on ERK dimerization. Consistent with this finding, DEL-22379 was ineffective in a RAS-driven melanoma model in zebrafish, in which ERK does not dimerize. Importantly, melanoma cells with NRAS overexpression or MEK1 mutations remained sensitive to DEL-22379 treatment, indicating that the antitumor activity of DEL-22379 is not affected by drug-resistance mechanisms associated with existing inhibitors of the RAS–ERK pathway. Overall, these data describe a specific and effective treatment for RAS–ERK-driven tumors and support the development of inhibitors of regulatory protein–protein interactions, rather than catalytic activities, to prevent tumor progression.

Herrero A, Pinto A, Colón-Bolea P, Casar B, Jones M, Agudo-Ibáñez L, et al. Small molecule inhibition of ERK dimerization prevents tumorigenesis by RAS-ERK pathway oncogenes. Cancer Cell 2015;28:170–82.

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