Editorial: Ras and Other GTPases in Cancer: From Basic to Applied Research

Department of Biochemistry and Molecular Biology, Boonshoft School of Medicine, Wright State University, Dayton, OH, United States, Department of Biology, ETH Zürich, Zürich, Switzerland, Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, Santander, Spain, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, Brazil

by reversible PTMs at their G4 and G5 motifs, including S-oxygenation, S-nitrosylation, monoubiquitylation, acetylation, and methylation. Osaka et al. provide a review discussing the mechanisms of these PTMs and propose that targeting these PTM mechanisms can be a good starting point for developing a new therapeutic approach for RAS-driven cancers.
Recently, direct K-RASG12C mutant inhibitors showed promising outcomes in clinical trials (Canon et al., 2019;Hallin et al., 2020), but since this mutant is found only in a small portion of K-RAS-driven cancers, pan-K-RAS therapies are still needed. Since most functional RAS proteins localize to the plasma membrane (PM), targeting the RAS-PM interaction represents a potential alternative strategy to disrupt RAS signaling activity. Zhou et al., in their review, summarizes the latest mechanistic insights on how different RAS isoforms undergo spatial segregation with different PM lipid species and how this could impact on the recruitment of their respective effectors and activation of different downstream signaling pathways. The authors further discuss the possibility of targeting RAS nanoclusters as a potential therapeutic approach to treat RAS pathologies. Moreover, Henkels et al. described how pharmacological agents disrupting K-RAS-PM interaction could be beneficial to block oncogenic K-RAS activity, thus representing clinical utility. K-RAS membrane organization is dependent on Calmodulin (CaM) and has significant impact on cancer stem cell tumorigenesis. Here, Okutachi et al. describes a novel CaM inhibitor, Calmirasone1, which has higher on-target inhibition on K-RAS compared to its off-target substrates including H-RAS and B-RAF. This discovery has exciting future applications for the interrogation of the cancer biology of CaM-associated K-RAS activities.
Tisi et al. describe a novel RAS inhibitor, cmp4, which exerts antiproliferative effects on cancer cells resistant to EGFR-aimed therapy. Cmp4 binds an extended Switch II pocket on H-RAS and K-RAS and induces a conformational change that abrogates guanine nucleotide exchange and impedes RAS effector binding. In this respect, cmp4 could provide a template for future drugs exploiting this promising mechanism of action.
Bartolacci et al. reviewed the recent advances concerning the relationship between RAS and lipid metabolism in cancer, describing how lipids and oxidative stress can either promote or sensitize to ferroptosis (i.e., an iron-dependent programmed cell death defined by the existence of oxidative stress and lipid peroxidation) RAS-driven cancers, which is still a controversial subject. The authors argue that RAS mutations have tissue-specific effects on metabolism, probably due to the intrinsic metabolic wiring present in distinct tumor types, and that the combination between ferroptosis inducers with existing chemotherapeutic agents, could be of potential clinical benefit.
Finally, RAS related proteins (RAP) are members of the RAS superfamily, sharing 50-60% sequence homology with RAS, and being involved in cell adhesion, migration, and polarity (Bokoch 1993). There are five different RAP family members, which are shown to be involved in the tumorigenesis of multiple cancer types (Bokoch 1993;Simanshu et al., 2017). Kumari et al. utilize authoritative multiomics databases to investigate the association of RAP gene family expression with molecular and clinicopathological features in hepatocellular carcinoma (HCC). Their study reveals significant associations of one of the RAP family members, RAP2A expression with several HCC pathways, including cell cycle-related pathways and metabolic pathways, suggesting RAP2A as a therapeutic target and prognostic biomarker in HCC.
Overall, this RT discusses the role of small GTPases in carcinogenesis and up-to-date strategies to block their oncogenic activities in cancer. We hope that the selected articles will inspire and motivate basic and clinical research scientists to further investigate several unanswered questions concerning the GTPases world. Despite being small proteins in size, their biological importance is substantial.

AUTHOR CONTRIBUTIONS
All Editorial authors contributed to the writing of this article, provided critical feedback, and approved its final version.