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Ref Type Journal Article
PMID (26267534)
Authors Herrero A, Pinto A, Colon-Bolea P, Casar B, Jones M, Agudo-Ibanez L, Vidal R, Tenbaum SP, Nuciforo P, Valdizan EM, Horvath Z, Orfi L, Pineda-Lucena A, Bony E, Keri G, Rivas G, Pazos A, Gozalbes R, Palmer HG, Hurlstone A, Crespo P
Title Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes.
Journal Vol Issue Date Pages Journal Short Title
Cancer cell 28 2 2015 Aug 10 170-82 Cancer Cell
URL
Abstract Text Nearly 50% of human malignancies exhibit unregulated RAS-ERK signaling; inhibiting it is a valid strategy for antineoplastic intervention. Upon activation, ERK dimerize, which is essential for ERK extranuclear, but not for nuclear, signaling. Here, we describe a small molecule inhibitor for ERK dimerization that, without affecting ERK phosphorylation, forestalls tumorigenesis driven by RAS-ERK pathway oncogenes. This compound is unaffected by resistance mechanisms that hamper classical RAS-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two understudied concepts in cancer therapy: (1) the blockade of sub-localization-specific sub-signals, rather than total signals, as a means of impeding oncogenic RAS-ERK signaling and (2) targeting regulatory protein-protein interactions, rather than catalytic activities, as an approach for producing effective antitumor agents.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
DEL-22379 DEL-22379 5 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
DEL-22379 ERK Inhibitor (pan) 21 DEL-22379 inhibits ERK dimerization, resulting in decreased extranuclear ERK signaling and potentially leading to reduced growth of ERK pathway-driven tumors (PMID: 26267534, PMID: 32377992).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E MAP2K1 I103N melanoma resistant Mirdametinib Preclinical - Cell culture Actionable In a preclinical study, overexpression of MAP2K1 I103N in melanoma cells harboring BRAF V600E resulted in insensitivity to growth inhibition by Gomekli (mirdametinib) in cell culture (PMID: 26267534). 26267534
BRAF V600E melanoma sensitive SCH772984 Preclinical Actionable In a preclinical study, SCH772984 inhibited growth of melanoma cell lines harboring BRAF V600E in culture (PMID: 26267534). 26267534
BRAF V600E MAP2K1 L115P melanoma resistant Mirdametinib Preclinical Actionable In a preclinical study, overexpression of MAP2K1 L115P in melanoma cells harboring BRAF V600E resulted in insensitivity to growth inhibition by Gomekli (mirdametinib) in cell culture (PMID: 26267534). 26267534
BRAF V600E NRAS G12V melanoma sensitive DEL-22379 Preclinical - Cell culture Actionable In a preclinical study, DEL-22379 inhibited growth of a melanoma cell line harboring BRAF V600E and over expressing NRAS G12V in culture (PMID: 26267534). 26267534
BRAF V600E colorectal cancer sensitive SCH772984 Preclinical Actionable In a preclinical study, SCH772984 inhibited growth of colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 26267534). 26267534
BRAF V600E MAP2K1 I103N melanoma sensitive DEL-22379 Preclinical - Cell culture Actionable In a preclinical study, DEL-22379 inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 I103N in culture (PMID: 26267534). 26267534
BRAF V600E MAP2K1 L115P melanoma sensitive DEL-22379 Preclinical - Cell culture Actionable In a preclinical study, DEL-22379 inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 L115P in culture (PMID: 26267534). 26267534
BRAF V600E melanoma conflicting Mirdametinib Preclinical - Cell culture Actionable In a preclinical study, Gomekli (mirdametinib) inhibited growth of melanoma cell lines harboring BRAF V600E in culture (PMID: 26267534). 26267534
BRAF V600E colorectal cancer sensitive Mirdametinib Preclinical Actionable In a preclinical study, Gomekli (mirdametinib) inhibited growth of colorectal cancer cell lines harboring BRAF V600E in culture (PMID: 26267534). 26267534
HRAS G12V melanoma sensitive CI-1040 Preclinical Actionable In a preclinical study CI-1040 (PD-184352) inhibited melanoma progression in a transgenic zebrafish model of melanoma expressing HRAS G12V (PMID: 26267534). 26267534
BRAF V600E colorectal adenocarcinoma sensitive DEL-22379 Preclinical - Pdx Actionable In a preclinical study, DEL-22379 inhibited tumor growth in a colorectal adenocarcinoma patient-derived xenograft model harboring BRAF V600E (PMID: 26267534). 26267534
BRAF V600E NRAS G12V melanoma resistant Vemurafenib Preclinical Actionable In a preclinical study, expression of NRAS G12V in melanoma cells harboring BRAF V600E conferred resistance to Zelboraf (vemurafenib) in culture (PMID: 26267534). 26267534
BRAF V600E melanoma sensitive DEL-22379 Preclinical - Cell line xenograft Actionable In a preclinical study, DEL-22379 inhibited growth of melanoma cells harboring BRAF V600E with high levels of ERK dimerization in culture and inhibited tumor progression in melanoma xenograft models harboring BRAF V600E (PMID: 26267534). 26267534