Mutational Activation of KRAS and BRAF in Colorectal Cancer

  • Katherine H. Pedone
  • Jennifer L. Sells
  • Channing J. Der


The failure of farnesyltransferase inhibitors to show antitumor activity against KRAS-mutant malignancies diminished enthusiasm for efforts to develop anti-Ras inhibitors for cancer treatment. However, two recent developments have rekindled interest in these endeavors. First, genome-wide exome sequencing verified that mutational activation of the KRAS gene is the most prevalent oncogene mutation in colorectal cancer (CRC). Second, a major step toward the application of personalized medicine for CRC was taken when mutant KRAS was established as a prognostic marker for resistance to epidermal growth factor receptor monoclonal antibody therapy. Thus, there is renewed and considerable interest in understanding the role of KRAS mutation in CRC progression and growth and in developing pharmacologic approaches for blocking aberrant K-Ras protein function for CRC treatment. Since the K-Ras protein itself is considered “undruggable,” current strategies to develop anti-K-Ras inhibitors have focused on antagonists of K-Ras downstream effector signaling. The frequent mutational activation of BRAF, which is mutually with KRAS activation, suggests that the encoded B-Raf serine/threonine kinase and activation of the ERK mitogen-activated protein kinase cascade is a key driver of mutant K-Ras-dependent CRC growth. In this review, we summarize the importance of mutant K-Ras and B-Raf in CRC growth and current efforts in targeting the Raf-MEK-ERK cascade for CRC treatment.


Akt GTPase Epidermal growth factor receptor ERK MEK Mitogen-activated protein kinase Phosphatidylinositol 3-kinase Raf 


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Katherine H. Pedone
    • 1
  • Jennifer L. Sells
    • 1
  • Channing J. Der
    • 1
  1. 1.University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer CenterChapel HillUSA

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