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Ref Type Journal Article
PMID (28986383)
Authors Brady DC, Crowe MS, Greenberg DN, Counter CM
Title Copper Chelation Inhibits BRAFV600E-Driven Melanomagenesis and Counters Resistance to BRAFV600E and MEK1/2 Inhibitors.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 77 22 2017 11 15 6240-6252 Cancer Res
URL
Abstract Text MEK1/2 and BRAFV600E inhibitors are used to treat BRAFV600E-positive melanoma, with other cancers under evaluation. Genetic perturbation of copper import or pharmacologic reduction of copper with the clinical copper chelator TTM inhibits MEK1/2 kinase activity and reduces BRAFV600E-driven tumorigenesis. In this study, we report that TTM inhibited transformed growth of melanoma cell lines resistant to BRAF or MEK1/2 inhibitors and enhanced the antineoplastic activity of these inhibitors. TTM also provided a survival advantage in a genetically engineered mouse model of melanoma, and when accounting for putative overdosing, trended toward an increase in the survival benefit afforded by BRAF inhibition. This effect was phenocopied by genetically inhibiting copper import in tumors, which was linked to a reduction in MAPK signaling. Thus, TTM reduces copper levels and MAPK signaling, thereby inhibiting BRAFV600E-driven melanoma tumor growth. These observations inform and support clinical evaluation of TTM in melanoma. Cancer Res; 77(22); 6240-52. ©2017 AACR.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
MAP2K1 D67N missense gain of function MAP2K1 D67N does not lie within any known functional domains of the Map2k1 protein (UniProt.org). D67N confers a gain of function to Map2k1 as demonstrated by increased Erk activation (PMID: 25049390, PMID: 29483135), increased Rsk phosphorylation (PMID: 25351745), and transformation in culture (PMID: 25351745, PMID: 36442478), and is associated with BRAF inhibitor resistance in the context of BRAF V600E in culture (PMID: 28986383). Y
MAP2K1 E203K missense gain of function MAP2K1 E203K lies within the protein kinase domain of the Map2k1 protein (UniProt.org). E203K confers a gain of function to the Map2k1 protein as demonstrated by constitutive Erk phosphorylation (PMID: 22197931, PMID: 29483135) and cell transformation in culture (PMID: 22197931), and is associated with drug resistance in the context of BRAF V600E in culture (PMID: 28986383). Y
MAP2K1 P264L missense unknown MAP2K1 P264L lies within the protein kinase domain of the Map2k1 protein (UniProt.org). P264L has been demonstrated to confer resistance to Raf inhibitors in the context of BRAF V600E in culture (PMID: 28986383), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Sep 2024). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E MAP2K1 P264L melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 P264L was resistant to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 Q56P melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 Q56P was resistant to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 Q56P melanoma conflicting Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 Q56P in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 Y134C melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 Y134C was resistant to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 C121S melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 C121S was resistant to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 E203K melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 E203K was resistant to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 D67N melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 D67N was resistant to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 C121S melanoma conflicting Trametinib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 C121S was resistant to Mekinist (trametinib) in culture (PMID: 28986383). 28986383
BRAF V600E NRAS Q61L melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing NRAS Q61L demonstrated resistance to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 E203K melanoma conflicting Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 E203K in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 F53S melanoma resistant Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 F53S was resistant to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 L115P melanoma conflicting Vemurafenib Preclinical - Cell culture Actionable In a preclinical study, a melanoma cell line harboring BRAF V600E and expressing MAP2K1 L115P was resistant to Zelboraf (vemurafenib) in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 P264L melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 P264L in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 F53S melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 F53S in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 Y134C melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 Y134C in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 L115P melanoma conflicting Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 L115P in culture (PMID: 28986383). 28986383
BRAF V600E MAP2K1 D67N melanoma sensitive Trametinib Preclinical - Cell culture Actionable In a preclinical study, Mekinist (trametinib) inhibited growth of a melanoma cell line harboring BRAF V600E and expressing MAP2K1 D67N in culture (PMID: 28986383). 28986383