Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma

• Published in: Cancer discovery 2013-02, Vol.3 (2), p.158-167
• Main Authors: Girotti, Maria R, Pedersen, Malin, Sanchez-Laorden, Berta, Viros, Amaya, Turajlic, Samra, Niculescu-Duvaz, Dan, Zambon, Alfonso, Sinclair, John, Hayes, Andrew, Gore, Martin, Lorigan, Paul, Springer, Caroline, Larkin, James, Jorgensen, Claus, Marais, Richard
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Line, Tumor; Cell Proliferation - drug effects; Dasatinib; Drug Resistance, Neoplasm - drug effects; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; Female; Humans; Immunoblotting; Indoles - pharmacology; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; Mice; Mice, Inbred NOD; Mice, Nude; Mice, SCID; Molecular Sequence Data; Mutation; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - metabolism; Pyrimidines - pharmacology; Signal Transduction - drug effects; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; STAT3 Transcription Factor - metabolism; Sulfonamides - pharmacology; Thiazoles - pharmacology; Vemurafenib; Xenograft Model Antitumor Assays
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-12-0386

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.