Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance

SIMPLE SUMMARY: Ras-GTPases play a key role in the control of fundamental cellular processes such as proliferation, survival, adhesion, and differentiation. These functions make them particularly relevant in the development and progression of numerous types of cancer. Activating mutations in some of these proteins are particularly relevant in colorectal cancer and largely determine its response to available therapies. In this review, we will discuss the role of Ras-GTPases in colorectal cancer, the strategies available to inhibit them and their implication in overcoming resistance to the therapies currently used in clinical practice. ABSTRACT: Colorectal cancer remains among the cancers with the highest incidence, prevalence, and mortality worldwide. Although the development of targeted therapies against the EGFR and VEGFR membrane receptors has considerably improved survival in these patients, the appearance of resistance means that their success is still limited. Overactivation of several members of the Ras-GTPase family is one of the main actors in both tumour progression and the lack of response to cytotoxic and targeted therapies. This fact has led many resources to be devoted over the last decades to the development of targeted therapies against these proteins. However, they have not been as successful as expected in their move to the clinic so far. In this review, we will analyse the role of these Ras-GTPases in the emergence and development of colorectal cancer and their relationship with resistance to targeted therapies, as well as the status and new advances in the design of targeted therapies against these proteins and their possible clinical implications.