New druggable targets in the Ras pathway?

Genes, 2021

Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designe...

Cancer biology & therapy

Mutationally activated and oncogenic versions of the ras genes were first identified in human tumors in 1982. This discovery prompted great interest in the development of anti-Ras strategies as novel, target-based approaches for cancer treatment. The three human ras genes represent the most frequently mutated oncogenes in human cancers. Consequently, a considerable research effort has been made to define the function of Ras in normal and neoplastic cells and to target Ras for cancer treatment. Among the anti-Ras strategies that are under evaluation in the clinic are pharmacologic inhibitors designed to prevent: (1) association with the plasma membrane (farnesyltransferase inhibitors), (2) downstream signaling (Raf and MEK protein kinase inhibitors), (3) autocrine growth factor signaling (EGF receptor inhibitors), or (4) gene expression (H-ras and c-raf-1). Although a number of these inhibitors have demonstrated potent anti-tumor activities in preclinical models, phase l-lll clinical...

Oncology & Hematology Review (US), 2015

Ras is a GTP-binding protein and is the most widely studied oncoprotein. To achieve its biological activity, it must undergo post-translation modification. Ras acts as a typical molecular switch. The GTP-bound Ras can activate several downstream effector pathways. Ras signaling regulates many important physiologic processes within a cell, such as cell cycle progression, survival, apoptosis, etc. Several studies have found mutation in Ras or its effectors in various types of tumors. Therefore, Ras or its downstream effectors can be attractive drug targets against various types of tumors in cancer therapeutics. Some therapeutic agents against Ras effectors, such as Raf, MEK1/2, PI3K, AKT etc., have successfully managed to enter into phase I and II trials. This targeted drug design could be envisaged in mainly four ways, such as prevention of Ras-GTP formation, covalent locking of the GDP-bound Ras, inhibition of Ras-effector interactions, or impairment of post-translational modificati...

Nature Reviews Cancer, 2003

RAS proteins: diversity and processing. The RAS proteins are members of a large superfamily of lowmolecular-weight GTP-binding proteins, which can be divided into several families according to the degree of sequence conservation. Different families are important for different cellular processes -the RAS family controls cell growth and the RHO family controls the actin cytoskeleton. Three members of the RAS family -HRAS, KRAS and NRAS -are found to be activated by mutation in human tumours 6 . These three members are very closely related, having 85% amino acid sequence identity and, although they function in very similar ways, some indications of subtle differences between them have recently come to light. The HRAS, KRAS and NRAS proteins are widely expressed, with KRAS being expressed in almost all cell types. Knockout studies have shown that Hras and Nras, either alone or in combination, are not required for normal development in the mouse, whereas Kras is essential 7 . This might reflect different molecular functions of the three proteins, but is more likely to reflect the more ubiquitous expression of KRAS.

Cold Spring Harbor Symposia on Quantitative Biology, 2005

Ras proteins play a direct causal role in human cancer and in other diseases. Mutant H-Ras, N-Ras, and K-Ras occur in varying frequencies in different tumor types, for reasons that are not known. Other members of the Ras superfamily may also contribute to cancer. Mutations also occur in downstream pathways, notably B-Raf, PTEN, and PI 3´ kinase: These pathways interact at multiple points, including cyclin D1, and act synergistically. In some cases mutations in Ras and effectors are mutually exclusive; in other cases, they coexist. Drugs blocking elements of the pathway are in different stages of clinical development. One of these, the Raf kinase/VEGF-R2 inhibitor Sorafenib, has already been approved for treatment of renal cancer and is being tested in other indications. However, therapeutic targets in the Ras pathway have not yet been fully validated as bona fide targets.

Central European Journal of Biology, 2013

Ras genes are pre-eminent genes that are frequently linked with cancer biology. The functional loss of ras protein caused by various point mutations within the gene, is established as a prognostic factor for the genesis of a constitutively active Ras-MAPK pathway leading to cancer. Ras signaling circuit follows a complex pathway, which connects many signaling molecules and cells. Several strategies have come up for targeting mutant ras proteins for cancer therapy, however, the clinical benefits remain insignificant. Targeting the Ras-MAPK pathway is extremely complicated due its intricate networks involving several upstream and downstream regulators. Blocking oncogenic Ras is still in latent stage and requires alternative approaches to screen the genes involved in Ras transformation. Understanding the mechanism of Ras induced tumorigenesis in diverse cancers and signaling networks will open a path for drug development and other therapeutic approaches.

Oncotarget, 2016

RAS proteins are the founding members of the RAS superfamily of GTPases. They are involved in key signaling pathways regulating essential cellular functions such as cell growth and differentiation. As a result, their deregulation by inactivating mutations often results in aberrant cell proliferation and cancer. With the exception of the relatively well-known KRAS, HRAS and NRAS proteins, little is known about how the interactions of the other RAS human paralogs affect cancer evolution and response to treatment. In this study we performed a comprehensive analysis of the relationship between the phylogeny of RAS proteins and their location in the protein interaction network. This analysis was integrated with the structural analysis of conserved positions in available 3D structures of RAS complexes. Our results show that many RAS proteins with divergent sequences are found close together in the human interactome. We found specific conserved amino acid positions in this group that map to the binding sites of RAS with many of their signaling effectors, suggesting that these pairs could share interacting partners. These results underscore the potential relevance of cross-talking in the RAS signaling network, which should be taken into account when considering the inhibitory activity of drugs targeting specific RAS oncoproteins. This study broadens our understanding of the human RAS signaling network and stresses the importance of considering its potential cross-talk in future therapies.

Nature Reviews Drug Discovery, 2014

In 1982, mutationally activated RAS genes were detected in human cancers, marking the first discovery of mutated genes in this disease 1 . Subsequent intensive sequencing of the cancer genome has revealed that, despite the identification of more than 500 validated cancer genes 2 (per the COSMIC (catalogue of somatic mutations in cancer) database), the three RAS genes (HRAS, NRAS and KRAS) still constitute the most frequently mutated oncogene family in human cancers (TABLE 1; see Supplementary information S1, S2 (tables)). The frequent mutation of RAS in three of the four most lethal cancers (lung, colon and pancreatic cancers) in the United States has spurred intense interest and effort in developing RAS inhibitors. However, despite more than three decades of effort by academia and industry, no effective RAS inhibitor has been approved, which has prompted a widely held perception that RAS oncoproteins are an 'undruggable' cancer target. Although past failures have dampened enthusiasm for the discovery of RAS inhibitors, mutated RAS proteins clearly merit continued attention. Given that the greatest success in signaltransduction-based therapies has been achieved against mutationally activated targets, there is now renewed hope that recent advances in understanding RAS function, together with new approaches and technologies, may finally have brought the holy grail of cancer research within reach 3 .

Cell, 2016

Oncogenic activation of RAS genes via point mutations occurs in 20%-30% of human cancers. The development of effective RAS inhibitors has been challenging, necessitating new approaches to inhibit this oncogenic protein. Functional studies have shown that the switch region of RAS interacts with a large number of effector proteins containing a common RAS-binding domain (RBD). Because RBD-mediated interactions are essential for RAS signaling, blocking RBD association with small molecules constitutes an attractive therapeutic approach. Here, we present evidence that rigosertib, a styryl-benzyl sulfone, acts as a RAS-mimetic and interacts with the RBDs of RAF kinases, resulting in their inability to bind to RAS, disruption of RAF activation, and inhibition of the RAS-RAF-MEK pathway. We also find that ribosertib binds to the RBDs of Ral-GDS and PI3Ks. These results suggest that targeting of RBDs across multiple signaling pathways by rigosertib may represent an effective strategy for inac...

Expert Opinion on Therapeutic Patents, 2012