KRAS as potential target in colorectal cancer therapy

Colorectal cancer (CRC) is among the most commonly diagnosed cancers affecting both genders in the world. It is characterized by genetic instability, which drives tumor formation via the activation of oncogenes, such as KRAS and B-RAF. Approximately 40% of CRC patients harbor the mutated KRAS oncogene as the predominant form of RAS mutation which plays a key role in the early development of cancer adenoma. The constitutively mutated K-Ras protein is able to bypass signals from its upstream effector, epidermal growth factor receptor (EGFR), thus rendering the existing anti-EGFR treatments (cetuximab and panitumumab) ineffective. However, there is no direct anti-KRAS treatment showing clinical benefits despite several decades of comprehensive efforts. To date, many efforts have been done to target the aberrant KRAS signaling at different levels including (1) inhibit RAS membrane association and (2) inhibit downstream KRAS effectors. The present chapter highlights the existing approaches in the management of KRAS-driven cancers by targeting RAS, and also discusses the potential drug candidates on this horizon.