RAS signaling pathways, mutations and their role in colorectal cancer

Abstract

Two of the main cellular pathways in which the RAS protein operates are the mitogen-activated protein kinases (MAPK) and phosphoinositide-3 kinase (PI3K) pathways. In a normal cell, these are important in controlling several functions, such as cell growth and survival. It becomes self-evident that these events will be disrupted in a malignant cell with a deregulated MAPK or PI3K pathway. Mutations in genes involved in these pathways and interacting with RAS, as well as RAS itself will be discussed. The second part of this review concentrates on how crucial RAS signaling is in colorectal cancer progression, with references to treatment response and prognosis when RAS or other related mutations are present.

Keywords: Genes; RAS; Colorectal neoplasms; Therapeutics; Mitogen-activated protein kinase signaling system

Core tip: This review outlines clearly the normal function of the mitogen-activated protein kinases and phosphoinositide-3 kinase cascades, in which the RAS proto-oncogene operates physiologically. It also describes the mutations in these pathways that lead to colorectal cancer (CRC), as well as other mutations outside these cascades affecting RAS function and also leading to CRC. The prognostic value of each mutation is assessed and linked to response rates to available biological treatments. Monoclonal antibodies under development are also briefly discussed.