JOURNAL ARTICLE
REVIEW

Mechanisms of resistance to RAF inhibition in melanomas harboring a BRAF mutation

Paul B Chapman
American Society of Clinical Oncology Educational Book 2013
23714462
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
23714462
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"