Trametinib, as compared with chemotherapy, improved rates of progression-free and overall survival among patients who had metastatic melanoma with a BRAF V600E or V600K mutation. (Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.).
HER2-directed therapies, such as trastuzumab and lapatinib, are important treatments for breast cancer. However, some tumors do not respond or develop resistance to these agents. We isolated and characterized multiple lapatinib-resistant, HER2-positive, estrogen receptor (ER)-positive breast cancer clones derived from lapatinib-sensitive BT474 cells by chronic exposure to lapatinib. We show overexpression of AXL as a novel mechanism of acquired resistance to HER2-targeted agents in these models. GSK1363089 ( foretinib), a multikinase inhibitor of AXL, MET, and vascular endothelial growth factor receptor currently in phase II clinical trials, restores lapatinib and trastuzumab sensitivity in these resistant cells that exhibit increased AXL expression. Furthermore, small interfering RNA to AXL, estrogen deprivation, or fulvestrant, an ER antagonist, decreases AXL expression and restores sensitivity to lapatinib in these cells. Taken together, these data provide scientific evidence to assess the expression of AXL in HER2-positive, ER-positive patients who have progressed on either lapatinib or trastuzumab and to test the combination of HER2-targeted agents and GSK1363089 in the clinic. [Cancer Res 2009;69(17):6871-8]
Purpose: Tumor-derived circulating cell-free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome.Experimental Design: Patients with BRAF V600 mutationpositive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined.Results: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K-positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAFmutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation-positive cfDNA in plasma had higher response rates to dabrafenib and trametinib.Conclusions: BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutationpositive tumors. The lack of circulating, BRAF mutation-positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome. Clin Cancer Res; 22(3); 567-74. Ó2015 AACR.
Summary Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
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