Reference Detail

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 L115P	melanoma	resistant	PD-0325901	Preclinical	Actionable	In a preclinical study, overexpression of MAP2K1 L115P in melanoma cells harboring BRAF V600E resulted in insensitivity to growth inhibition by PD-0325901 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 I103N	melanoma	resistant	PD-0325901	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 PD-0325901 in cell culture (PMID: 26267534).	26267534
BRAF V600E	colorectal cancer	sensitive	PD-0325901	Preclinical	Actionable	In a preclinical study, PD-0325901 inhibited growth of colorectal cancer cell lines harboring BRAF V600E in culture (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
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	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
BRAF V600E	melanoma	conflicting	PD-0325901	Preclinical - Cell culture	Actionable	In a preclinical study, PD-0325901 inhibited growth of melanoma cell lines harboring BRAF V600E 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 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 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 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