Molecular Characterization of Acquired Resistance to the BRAF Inhibitor Dabrafenib in a Patient with BRAF-Mutant Non–Small-Cell Lung Cancer Charles M.

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Presentation transcript:

Molecular Characterization of Acquired Resistance to the BRAF Inhibitor Dabrafenib in a Patient with BRAF-Mutant Non–Small-Cell Lung Cancer Charles M. Rudin, MD, PhD, Kelvin Hong, MD, Michael Streit, MD Journal of Thoracic Oncology Volume 8, Issue 5, Pages e41-e42 (May 2013) DOI: 10.1097/JTO.0b013e31828bb1b3 Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Metastatic lung cancer response to dabrafenib. Serial computed tomography scans of the right lung are shown, pretreatment, at first ontreatment assessment (6 weeks) and after 4 months of therapy. Multiple pulmonary nodules and a malignant effusion are evident at baseline. The partial response at 6 weeks was confirmed on multiple subsequent scans, before disease progression as described. Journal of Thoracic Oncology 2013 8, e41-e42DOI: (10.1097/JTO.0b013e31828bb1b3) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 MAPK signaling in nontransformed and cancer cells. Left: wild-type signaling. In most cells the MAPK pathway is tightly regulated by ligand-dependent activation of receptor tyrosine kinases, which signal through any of three RAS family GTPs (N-, K-, and H-RAS, depending on the cell type). RAS-GTP in turn triggers dimerization and activation of RAF family tyrosine kinases (A-, B-, and C-RAF), leading to activation of the downstream proliferative signaling pathway. Middle: oncogenic BRAF signaling. The BRAFV600E mutation promotes kinase activity as a monomer and is independent of RAS regulation, leading to potent and constitutive activation of the pathway. Such cells may be highly responsive to BRAF inhibitor therapy. Right: secondary KRAS mutation. A KRASG12D mutation locks KRAS in the GTP-bound (ON) configuration, independent of receptor tyrosine kinase regulation. Oncogenic KRAS activates multiple downstream pathways regulating proliferation and survival (not shown here). Among other effects, it may bypass inhibition of BRAFV600E by BRAF inhibitors, through stimulating dimerization of other RAF family members, leading to downstream activation of the MAPK pathway. BRAF, ; KRAS, ; MAPK, mitogen-activated protein kinase; GTP, . Journal of Thoracic Oncology 2013 8, e41-e42DOI: (10.1097/JTO.0b013e31828bb1b3) Copyright © 2013 International Association for the Study of Lung Cancer Terms and Conditions