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Inhibiting EGF Receptor or SRC Family Kinase Signaling Overcomes BRAF Inhibitor Resistance in Melanoma

2012; American Association for Cancer Research; Volume: 3; Issue: 2 Linguagem: Inglês

10.1158/2159-8290.cd-12-0386

2159-8290

María Romina Girotti, Malin Pedersen, Berta Sánchez-Laorden, Amaya Virós, Samra Turajlic, Dan Niculescu‐Duvaz, Alfonso Zambon, John Sinclair, Andrew Hayes, Martin Gore, Paul Lorigan, Caroline J. Springer, James Larkin, Claus Jørgensen, Richard Marais,

Cytokine Signaling Pathways and Interactions

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.