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Ref Type Journal Article
PMID (23242808)
Authors Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S, Niculescu-Duvaz D, Zambon A, Sinclair J, Hayes A, Gore M, Lorigan P, Springer C, Larkin J, Jorgensen C, Marais R
Title Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma.
Journal Cancer discovery
Vol 3
Issue 2
Date 2013 Feb
URL
Abstract Text We generated cell lines resistant to BRAF inhibitors and show that the EGF receptor (EGFR)-SRC family kinase (SFK)-STAT3 signaling pathway was upregulated in these cells. In addition to driving proliferation of resistant cells, this pathway also stimulated invasion and metastasis. EGFR inhibitors cooperated with BRAF inhibitors to block the growth of the resistant cells in vitro and in vivo, and monotherapy with the broad specificity tyrosine kinase inhibitor dasatinib blocked growth and metastasis in vivo. We analyzed tumors from patients with intrinsic or acquired resistance to vemurafenib and observed increased EGFR and SFK activity. Furthermore, dasatinib blocked the growth and metastasis of one of the resistant tumors in immunocompromised mice. Our data show that BRAF inhibitor-mediated activation of EGFR-SFK-STAT3 signaling can mediate resistance in patients with BRAF-mutant melanoma. We describe 2 treatments that seem to overcome this resistance and could deliver therapeutic efficacy in patients with drug-resistant BRAF-mutant melanoma.Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratified for treatment. However, as with conventional therapies, patients often develop acquired resistance to targeted therapies, and a proportion of patients are intrinsically resistant and fail to respond despite the presence of an appropriate driver oncogene mutation. We found that the EGFR/SFK pathway mediated resistance to vemurafenib in BRAF -mutant melanoma and that BRAF and EGFR or SFK inhibition blocked proliferation and invasion of these resistant tumors, providing potentially effective therapeutic options for these patients.

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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
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V600E melanoma sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited cell invasion, cell signaling, and proliferation in human melanoma cell lines harboring BRAF V600E that are resistant to Braf inhibition in culture and in animal models (PMID: 23242808). 23242808
BRAF V600E melanoma sensitive S3I-201 Preclinical Actionable In a preclinical study, S3I-201 inhibited cell invasion and Stat3 signaling in human melanoma cell lines harboring BRAF V600E that are resistant to Braf inhibition in culture (PMID: 23242808). 23242808
BRAF V600E melanoma sensitive Saracatinib Preclinical Actionable In a preclinical study, saracatinib inhibited proliferation of human melanoma cell lines harboring BRAF V600E that are resistant to Braf inhibition in culture (PMID: 23242808). 23242808
BRAF V600E melanoma sensitive Gefitinib + PLX4720 Preclinical Actionable In a preclinical study, Iressa (gefitinib) in combination with PLX4720 inhibited proliferation and tumorigenicity in human melanoma cell line harboring BRAF V600E and resistant to Braf inhibition in culture and in animal models (PMID: 23242808). 23242808