After a decade of success in targeting molecular alterations in non–small cell lung cancer (NSCLC), researchers are focusing on small molecules that attack the BRAF cell-signaling network directly or in combination with other inhibitors.
Numerous studies have now confirmed that BRAF
mutations represent a 1% to 4% slice of the genetic pie of NSCLC. These mutations are most renowned for their role in melanoma development and researchers are hoping to translate the success of BRAF
-targeted therapies in this cancer type to NSCLC.
Several of these drugs have demonstrated impressive efficacy in BRAF
-mutant NSCLC patient populations and have been awarded breakthrough therapy designations from the FDA. The types of BRAF
mutations in NSCLC may differ from those observed in melanoma, and a greater understanding of these nuances and their sensitivity to currently available drugs is a central focus of ongoing research.
A Model of Personalized Cancer Therapy
Thanks to advances in genomic sequencing, a targetable molecular alteration can now be identified in more than half of all patients with NSCLC, the most common histological subtype of lung cancer. The ability to detect these drivers with diagnostic tests and to pair them with targeted therapies has revolutionized the treatment of NSCLC.
The best studied drivers are the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), and the success of small molecule inhibitors targeting these tyrosine kinase receptors has served as a model of targeted drug development in oncology.
BRAF's Place in Signaling Network
Growth factors that bind to their receptors (EGFR, MET, ERBB3, ERBB2, and FGFR) promote RAS activity, which in turn sets off a cell-signaling cascade that includes BRAF activation.
Nussinov R, Jang H, Tsai CJ. The structural basis for cancer treatment. Oncotarget. 2014;5(17):7285-302.
A number of other kinases involved in cell signaling pathways have been implicated in the development of NSCLC, among them the BRAF protein, a core component of the mitogen- activated protein kinase (MAPK) signaling pathway that is central to driving the runaway proliferation of cancer cells.
Besides a predominance in the adenocarcinoma subtype of NSCLC, no other defining clinical features of BRAF
-mutant NSCLC have yet been carved out. Perpetuating Growth Signals BRAF is one of three members of the RAF family of proteins that serve as kinase enzymes, which phosphorylate key serine or threonine residues within the amino acid sequence of other proteins. In this way, they propagate signals from the cell membrane to the nucleus through the MAPK pathway. One of the first steps in the MAPK pathway involves the activation of the RAS protein, a small GTPase that switches between a guanosine diphosphate (GDP)- bound “off” state and a guanosine triphosphate (GTP)-bound "on" state. RAS can be activated by signals generated from growth factors, cytokines, and hormones binding to their respective receptors on the cell surface.
Once RAS is switched on, it recruits RAF to the cell membrane, where it is also activated, allowing it to subsequently phosphorylate and activate the next kinase in the chain. Ultimately, the cascade of phosphorylation events that make up the MAPK pathway leads to the ERK protein being shifted into the nucleus, where it stimulates the transcription of a number of different gene targets that orchestrate the cellular responses to the initial signal received at the membrane.
BRAF is a proto-oncogene because its key role in the MAPK pathway makes it vulnerable to mutations that cause a change in the DNA sequence leading to the production of an altered protein, which impacts the normal function of the cell and can contribute to cancer development.
Studies suggest that somatic mutations in BRAF
occur in just under 10% of all human cancers. Most notably, BRAF
mutations are found in around half of malignant melanomas. In the vast majority of cases, the BRAF mutations observed in melanoma result in a single amino acid change within the kinase domain, in which a valine is substituted for a glutamine at position 600 (V600E).
This mutation occurs with the kinase domain and the insertion of a negatively charged amino acid is thought to mimic phosphorylation, resulting in increased kinase activity. Since BRAF is a central player in the MAPK pathway, the pathway becomes more highly activated in the presence of these activating mutations.