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

Abstract

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 specifi city 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 effi cacy in patients with drug-resistant BRAF-mutant melanoma. SIGNIFICANCE:Therapies that target the driver oncogenes in cancer can achieve remarkable responses if patients are stratifi ed 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. Cancer Discov; 3(2);

EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E–Mutant NSCLC Cell Lines

“…The most interesting and novel finding of our study is that ERK1/2 activation, the critical contributor to BRAF inhibitor resistance, is independent of MEK1/2 activity but partly dependent on RIP2 kinase activity, which distinguishes BRAF inhibitor-resistant NSCLC V600E from BRAF inhibitor-resistant melanoma V600E . To our knowledge, various acquired resistance mechanisms to BRAF inhibitors have been reported to date (20): alternative splicing of BRAF (14), BRAF amplification (21), CRAF overexpression (22), and activation of EGFR signaling (15,23,24). In the former mechanism reported in melanoma V600E , p61 splicing variant (p61BRAF)-driven resistance to BRAF inhibitors reactivated MEK-ERK signaling through enhanced dimerization of the aberrant BRAF isoform (14).…”

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

“…Despite the presence of the BRAF V600E mutation, around 20% to 40% of patients do not initially respond to vemurafenib because of intrinsic resistance to BRAF inhibition (20). One mechanism of intrinsic resistance involves overexpression of the MAPK family member COT, which activates ERK signaling cascades through MEK-dependent mechanisms that are not reliant on RAF (21).…”

Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma

“…The BRAF oncogene is mutated in ∼50% of melanomas, and although BRAF and MEK inhibitors increase survival in these patients (3)(4)(5), even when they are combined most patients develop resistance after 6 to 12 months (6)(7)(8). Antibody antagonists of CTLA-4 and PD-1 provide survival benefi ts in a subset of patients (9)(10)(11) and even better responses when combined ( 10,11 ).…”