Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLC(V600E) with acquired resistance to BRAF inhibitors.
Current evidence suggests that the mandatory tests to conduct in all patients with advanced NSCLC are for EGFR and BRAF mutations, ALK and ROS1 rearrangements and PD-L1 expression.
Dabrafenib is a potent and selective inhibitor of BRAF-mutant kinase that is approved, as monotherapy or in combination with trametinib (mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor), for unresectable or metastatic BRAF-mutated melanoma, advanced non-small cell lung cancer and anaplastic thyroid cancer harbouring the BRAF<sup>V600E</sup> mutation.
Direct inhibition of mutant B-Raf proto-oncogene, serine/threonine kinase (BRAF) and/or downstream mitogen-activated protein kinase kinase (MEK) has the potential to change the course of the disease for patients with <i>BRAF</i>-mutant NSCLC, as it has in <i>BRAF</i>-mutant melanoma.
Downregulation of BRAF activated non-coding RNA is associated with poor prognosis for non-small cell lung cancer and promotes metastasis by affecting epithelial-mesenchymal transition.
Due to the rarity of BRAFV600E mutation, no randomized study has compared the combination targeted therapy dabrafenib + trametinib with other second-line treatments for advanced or metastatic non-small-cell lung cancer (NSCLC).
EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (formalin-fixed paraffin-embedded tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions.
Here we demonstrated that a combination of MEK and BRAF inhibitors overcomes paradoxical MAPK activation (induced by BRAF inhibitors) in BRAF-wt/RAS-mut NSCLC and PDAC in vitro.
Here we took advantage of the French National Cancer Institute Program of systematic molecular profiling of metastatic lung cancer, to collect clinical characteristics and analyze the outcome of consecutive patients with NSCLC harboring BRAF mutations at the Lyon University Hospital laboratory between February 2012 and October 2014.
Here, in this review, we outline the preclinical and clinical data for BRAF and MEK inhibitor combination treatment for NSCLC patients with BRAFV600E mutation.
Here, we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing: BRAFV600E for vemurafenib in melanoma; EML4-ALK for crizotinib and EGFR for erlotinib and gefitinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; ERBB2 (HER2/neu) for trastuzumab in breast cancer; BCR-ABL for tyrosine kinase inhibitors in chronic myeloid leukemia; and PML/RARα for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia.
Herein, beyond describing a cohort of BRAF mutant NSCLC patients and functionally analyzing 13 tumor-derived BRAF mutations, we demonstrate that both types of non-V600 BRAF mutations can be sensitive to clinically relevant doses of Dabrafenib and Trametinib in HEK293T cells, in lung epithelial cellular model (BEAS-2B) and in human cancer cell lines harboring non-V600 BRAF mutations.