KRAS – An Evolving Cancer Target


Austin J Cancer Clin Res 2014;1(1): 1004.

KRAS – An Evolving Cancer Target

Na Ye and Jia Zhou

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston

*Corresponding author: Jia Zhou, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA

Received: December 20, 2013; Accepted: January 10, 2014; Published: January 12, 2014

The Ras proteins play an important role in cell growth, differentiation, proliferation and survival by regulating diverse cellular pathways. KRAS is the most frequently mutated class of Ras superfamily in all human cancers (21.6%), thus stimulating intensive efforts in developing effective approaches including new drugs to combat various KRAS–mutant–driven cancers. While accumulating evidence supports KRAS as an evolving cancer target, no effective anti–KRAS medications have yet been approved for clinical use to date. Here, we present a concise overview of advances with respect to indirect and direct strategies targeting aberrant KRAS signaling.

The KRAS gene (Ki–ras2 Kirsten RAt Sarcoma viral oncogene homolog), which encoded an approximately 21kDa monomeric, membrane–localized GTPase transforming protein called KRAS, was first discovered and identified as a human oncogene in 1982 [1]. KRAS protein exists as two splice variants, KRAS4A and KRAS4B, all of which belong to the Ras superfamily functioning as molecular switches in regulating diverse cellular pathways for cell growth, differentiation, proliferation and survival. KRAS4B as the dominant isoform is widely expressed in human cells. Ras normally cycles between an active, GTP–bound “off” state and an inactive, GDP–bound “on” state. The conversions are strictly controlled by guanine nucleotide exchange factors (GEFs) and GTPase–activating proteins (GAPs), which are influenced by a number of upstream cell surface receptors such as receptor tyrosine kinases, serpentine receptors, integrins, cytokine receptors and heterotrimeric G–proteins. Activated Ras then targets a number of downstream effectors including PI3K, RAF kinases, MEKK1, Rin 1 and RalGEFs to produce pleiotropic cellular effects. However, the wild–type KRAS gene is a tumor suppressor that can lose this critical function during tumor progression in many types of cancers [2]. Once KRAS mutates, it can become oncogenic and contribute to driving malignant transformation by fixing the protein in a constitutively “on” state. Single point mutations of Ras occur most commonly in residue G12, G13 and Q61, and have been found in 30% of all human tumors. Among these, activating mutations of KRAS are one of the most frequently mutated Ras isoforms in human cancers with the highest prevalence in pancreatic adenocarcinomas (90%), colorectal cancers (45%) and lung cancers (35%) [3].

Based on the important role of Ras in oncogenesis and the prevalence of KRAS mutations in human cancers, KRAS represents an intriguing and promising cancer research target. Over the past decade, KRAS has received a resurgence of interest due to the outcomes of cancer–genomics studies (Figure 1). A number of indirect and direct strategies have been developed to target aberrant KRAS signaling at different levels for inhibiting tumor growth, survival and metastasis. These strategies [4,5] include inhibiting upstream cell surface receptors, inhibiting membrane localization through post–translational modification or trafficking [6], blocking Ras⁄GEFs interactions, enhancing Ras⁄GAP interactions, and directly targeting oncogenic KRAS, as well as inhibiting Ras downstream effectors.

Citation: Ye N, Zhou J. KRAS – An Evolving Cancer Target. Austin J Cancer Clin Res 2014;1(1): 1004. ISSN 2381-909X