cancers Review Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance Anxo Rio-Vilariño , Laura del Puerto-Nevado, Jesús García-Foncillas * and Arancha Cebrián*   Citation: Rio-Vilariño, A.; del Puerto-Nevado, L.; García-Foncillas, J.; Cebrián, A. Ras Family of Small GTPases in CRC: New Perspectives for Overcoming Drug Resistance. Cancers 2021, 13, 3757. https:// doi.org/10.3390/cancers13153757 Academic Editor: Paulo Matos Received: 25 June 2021 Accepted: 23 July 2021 Published: 26 July 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Translational Oncology Division, Hospital Universitario Fundación Jimenez Diaz, 28040 Madrid, Spain; anxo.rio@quironsalud.es (A.R.-V.); lpuerto@oncohealth.eu (L.d.P.-N.) * Correspondence: jesus.garciafoncillas@oncohealth.eu (J.G.-F.); arancha.cebrian@oncohealth.eu (A.C.); Tel.: +34-915-50-48-00 (J.G.-F.) 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. Keywords: colorectal cancer; drug resistance; EGFR targeted therapies; Ras-GTPases 1. Introduction According to the Global Cancer Observatory (GLOBOCAN) reports, colorectal cancer (CRC) ranks third in the number of diagnoses, representing 10% of the total, and being the second one in prevalence and mortality. This means more than 1.4 million new cases and near 1 million deaths worldwide in 2020 [1]. However, screening and early diagnosis programs are increasing the detection of tumours at earlier stages, significantly increasing the overall survival of patients [2]. 1.1. Colorectal Carcinogenesis More than 95% of all CRCs diagnosed worldwide occur spontaneously, while the remaining small proportion has hereditary components associated with certain syndromes such as Lynch, Muir-Torre or Turcot syndromes [3,4]. Within sporadic cancers, most (up to 85%) begin with the formation of a benign adenoma [5], because of the accumulation of changes related to chromosomal instability (CIN) or microsatellite instability (MSI) [6]. CIN events involve an increased propensity for errors in chromosome segregation during mitosis, leading to the appearance of aneuploidies that is characteristic of many cancers [7], Cancers 2021, 13, 3757. https://doi.org/10.3390/cancers13153757 https://www.mdpi.com/journal/cancers