Impact of KRAS and BRAF gene mutations on targeted therapies in colorectal cancer.

In Journal of Clinical Oncology, Price et al present an analysis of the predictive and prognostic impact of KRAS and BRAF gene mutations in patients with metastatic colorectal cancer. In this study, patients were randomly assigned to receive treatment with the fluorouracil prodrug capecitabine either alone or in combination with bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor-A (VEGF). The authors conclude that although KRAS mutations are not prognostic, patients with BRAF mutations have significantly worse survival. However, neither mutation was found to modulate outcome when bevacizumab was added to fluorouracil-based therapy. This Understanding the Pathway article provides an opportunity to gain a better understanding of the biology underlying K-Ras and B-Raf. Recurrent somatic mutations in KRAS and BRAF are found in colorectal carcinoma as well as other cancer types. Both of these genes encode proteins that are part of the mitogen-activated protein kinase (MAPK) pathway, a signaling cascade connecting receptors on the cell membrane (which receive external proliferative signals) to the downstream machinery regulating cellular growth. In the normal physiologic setting, this pathway is carefully regulated to prevent excessive cellular proliferation. However, this exquisite growth regulation is often bypassed in cancer through mutations within this pathway— mutations that either activate key signaling proteins (eg, Ras or Raf) or inactivate safeguard proteins that downregulate this signaling (eg, phosphatase and tensin homolog). Even a cursory inspection of the MAPK and intersecting pathways quickly reveals a who’s who of many commonly mutated genes in cancer (Fig 1). The proximal points of the pathway are the cell surface receptors, such as the epidermal growth factor receptor. On binding of ligand to the extracellular component of the receptor (by mitogens such as epidermal growth factor), the intracellular portion (which contains the kinase domain) becomes activated. The activated kinase adds phosphate groups to intracellular signaling proteins, thus activating the relevant downstream cascades. The phosphoinositide 3-kinase and MAPK pathways are among the most important signaling arms downstream of receptor tyrosine kinases. Within the MAPK pathway, cellular intermediates link the cell surface tyrosine kinase activity to Ras, a key hub of cellular activity and a classic oncoprotein. Proteins composing the Ras family (K-Ras, N-Ras, and H-Ras) all act in a similar fashion; they are guanosine triphosphatase (GTPase) proteins, the activity of which is governed by binding to GTP (active state) or by hydrolysis of GTP to guanosine diphosphate (GDP; inactive state). When activated, Ras proteins augment multiple downstream signaling pathways, including the MAPK pathway, which consists of a cascade of signaling, starting with Raf activation (Fig 1). Like Ras, Raf refers to a family of proteins (A-Raf, B-Raf, and C-Raf)—in this case, serine/threonine kinases whose signaling ultimately activates a transcriptional program regulating cell growth. RAS mutations are highly recurrent in human cancers. For example, KRAS mutations are seen in approximately 30% of colorectal PTEN PI3-K