Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation Journal Article
| Author: | Chapman, P. B. |
| Article Title: | Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation |
| Abstract: | Treatment of V600E/K BRAF-mutated melanomas with RAF inhibitors (either vemurafenib or dabrafenib) results in rapid and dramatic responses in most patients-results that are associated with improved progression-free survival (PFS) and in the case of vemurafenib, overall survival (OS). However, resistance develops at a median time of approximately 6 months. Understanding the mechanisms of resistance is critical to develop strategies to prolong PFS and OS. Negative feedback mechanisms inherent in the MAPK pathway serve to modulate responses to these drugs. However, genetic changes develop within the tumor, which lead to reactivation of the MAPK and resistance to these drugs. The mechanisms that have been demonstrated in many patients by multiple investigators are (1) development of an activating mutation in NRAS, and (2) appearance of a BRAFV600E splice variant that encourages RAF dimerization. Several other mechanisms of resistance have also been described in individual patients or in preclinical models of resistance. In addition, there is evidence that activation of parallel pathways, such as the PI3K/AKT pathway, may represent another mechanism of resistance. Understanding the various mechanisms of resistance will inform our attempts to prevent resistance to RAF inhibitors. |
| Keywords: | signal transduction; protein kinase b; disease-free survival; genetics; mutation; antineoplastic agents; clinical trials as topic; disease free survival; antineoplastic agent; melanoma; map kinase signaling system; protein kinase inhibitor; neoplasm proteins; enzyme activation; drug resistance; enzymology; drug resistance, neoplasm; phosphatidylinositol 3 kinase; physiology; protein kinase inhibitors; gene expression regulation; gene expression regulation, neoplastic; sulfonamide; sulfonamides; tumor protein; proto-oncogene proteins c-akt; feedback system; indoles; indole derivative; feedback, physiological; b raf kinase; proto-oncogene proteins b-raf; imidazoles; imidazole derivative; clinical trial (topic); phosphatidylinositol 3-kinases; vemurafenib; drug effects; dabrafenib; akt1 protein, human; oximes; humans; human; antagonists and inhibitors; oxime |
| Journal Title: | American Society of Clinical Oncology Educational Book |
| Volume: | 33 |
| ISSN: | 1548-8756 |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2013-01-01 |
| Start Page: | e80 |
| End Page: | e82 |
| Language: | English |
| DOI: | 10.1200/EdBook_AM.2013.33.e80 |
| PUBMED: | 23714462 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Review -- Export Date: 3 February 2016 -- Source: Scopus |
