Data from Elucidating Distinct Roles for <i>NF1</i> in Melanomagenesis

Abstract

<div>Abstract<p><i>BRAF</i> mutations play a well-established role in melanomagenesis; however, without additional genetic alterations, tumor development is restricted by oncogene-induced senescence (OIS). Here, we show that mutations in the <i>NF1</i> tumor suppressor gene cooperate with <i>BRAF</i> mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, <i>Nf1</i> mutations suppress <i>Braf</i>-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. <i>Nf1</i> mutations function by deregulating both phosphoinositide 3-kinase and extracellular signal–regulated kinase pathways. As such, <i>Nf1/Braf</i>–mutant tumors are resistant to BRAF inhibitors but are sensitive to combined inhibition of mitogen-activated protein/extracellular signal–regulated kinase kinase and mTOR. Importantly, <i>NF1</i> is mutated or suppressed in human melanomas that harbor concurrent <i>BRAF</i> mutations, <i>NF1</i> ablation decreases the sensitivity of melanoma cell lines to BRAF inhibitors, and NF1 is lost in tumors from patients following treatment with these agents. Collectively, these studies provide mechanistic insight into how <i>NF1</i> cooperates with <i>BRAF</i> mutations in melanoma and show that <i>NF1</i>/neurofibromin inactivation may have an impact on responses to targeted therapies.</p><p><b>Significance:</b> This study elucidates the mechanism by which <i>NF1</i> mutations cooperate with different <i>BRAF</i> mutations in melanomagenesis and shows that <i>NF1</i>/neurofibromin loss may desensitize tumors to BRAF inhibitors. <i>Cancer Discov; 3(3); 338–49. ©2012 AACR.</i></p><p>See related commentary by Gibney and Smalley, p. 260</p><p>This article is highlighted in the In This Issue feature, p. 239</p></div>