Ras proteins are a family of monomeric GTPases found ubiquitously in almost all animal cell types. They act as signaling hubs within the cell, interacting with different intracellular signaling proteins to amplify signals down different downstream paths within the cell. These downstream paths ultimately regulate the transcription of genes controlling cell growth, differentiation and survival. Because of this, uncontrolled Ras signaling can lead to cancer development: three human Ras genes,  KRAS, NRAS and HRAS, are the most frequently mutated or dysregulated leading to oncogenic transformation¹.

Overview of Ras signaling

The Ras signaling cascade can be activated by various cellular receptors – including receptor tyrosine kinases, G-protein coupled receptors, and integrins – which induce activation of Ras via a series of scaffolding proteins. Ras proteins exist in two conformations: active when bound to guanosine triphosphate (GTP), and inactive when bound to guanosine diphosphate (GDP). This mechanism allows Ras proteins to function as binary molecular switches, acting as a master regulator by turning downstream pathways on or off.

Many of these pathways are vital for the control of cell fate: the MAPK/ERK cascade controls the transcription of genes involved in cell growth and division, and the PI3K/AKT pathway inhibits apoptosis. Through these and other pathways, Ras ultimately controls the expression of genes relating to cell proliferation, cell survival, differentiation, development, cell cycle control, cell motility, and apoptosis². As a result, regulating Ras activity is essential for regulating cell fate.

Regulation of Ras activity relies on cycling between its active and inactive forms. Guanine nucleotide Exchange Factors (GEFs), such as Son of sevenless (SOS) and RAS-specific guanyl-nucleotide-releasing factor (RASGRF), stimulate the release of GDP from Ras and the uptake of GTP, which activates Ras and leads to downstream signaling. By contrast, Ras GTPase-Activating Proteins (GAPs) increase the rate of hydrolysis of GTP by Ras: as a GTPase, Ras has intrinsic hydrolyzing ability, but this is too slow to be efficient. By catalyzing Ras hydrolysis, GAPs stimulate conversion to the inactive GDP-bound form of Ras, inhibiting its activity.

What to expect from our Ras pathway poster

Our poster shows various Ras signaling pathways within the cell, and demonstrates how extracellular signals cascade down intracellular pathways to converge on effector proteins and transcription factors that regulate cell processes like apoptosis and proliferation.

Ras in cancer

Ras is a master regulator of cell growth and survival, making it a uniquely potent promotor of cancer development and survival when dysregulated. In normal cells, Ras-mediated signaling is regulated by balancing cycling between the active and inactive forms of Ras. This balance can be disturbed through inappropriate activation of Ras by mutations in either genes coding for proteins upstream of Ras, or Ras itself. For example, constant upstream signaling can over-activate Ras, rendering it resistant to the hydrolyzing action of GAPs, significantly reducing the rate of GTP hydrolysis and increasing the proportion of active GTP-bound Ras in the cell³.

Ras itself can also become mutated to be constituently active: these mutations prevent GTP hydrolysis by Ras altogether, locking the protein into a permanently active state. These mutations, most commonly occurring at codons 12 and 61, are most prevalent in KRAS and NRAS⁴. Constitutive activation of Ras causes upregulation of its downstream pathways, ultimately leading to increased cell proliferation and metastasis, and decreased apoptosis. Mutations leading to permanent Ras activation are found in 20-25% of all human tumors, but can be as high as 90% in some hard-to-treat cancers like pancreatic cancer⁵. It is thought that mutations in KRAS alone account for approximately one million deaths a year worldwide⁶. As a result, Ras inhibitors are being studied as a treatment for cancer and other ‘Rasopathies’, such as Neurofibromatosis 1.

Ras as a therapeutic target

Tumor-lysing viruses that target cells with an activated Ras pathway have been developed as cancer therapeutics: these include Reolysin, a formulation of reovirus, and FusOn-H2, a herpes simplex virus-based agent⁷.

Treatments are also being developed that inhibit mutated KRAS: these include the covalent KRAS-G12C inhibitor sotorasib (approved by the FDA for the treatment of non-small cell lung cancer⁸) and siG12D LODER, a treatment based on siRNA anti-mutated KRAS⁹. Resistance to Ras-targeted therapies is common and new combination therapies are being developed to overcome common routes to resistance^10,11.

References

1. Prior, I. A.,, Hood, F. E. &, Hartley, J. L. The frequency of Ras mutations in cancer. Cancer Research  80 ,2969-2974 (2020)
2. Crespo, P. &, Leon, J. Ras proteins in the control of the cell cycle and cell differentiation. Cellular and Molecular Life Sciences CMLS  57 ,1613-1636 (2000)
3. Reuter, C. W.,, Morgan, M. A. &, Bergmann, L. Targeting the Ras signaling pathway: A rational, mechanism-based treatment for hematologic malignancies? Blood  96 ,1655-1669 (2000)
4. Gimple, R. C. &, Wang, X. Ras: Striking at the core of the oncogenic circuitry. Frontiers in Oncology  9 , (2019)
5. Downward, J. Targeting Ras signalling pathways in cancer therapy. Nature Reviews Cancer  3 ,11-22 (2003)
6. Simanshu, D. K.,, Nissley, D. V. &, McCormick, F. Ras proteins and their regulators in human disease. Cell  170 ,17-33 (2017)
7. Thirukkumaran, C. &, Morris, D. G. Oncolytic Viral therapy using reovirus Gene Therapy of Cancer ,607-634 (2009)
8. Sotorasib approved for KRAS G12C-mutated non-small cell lung cancer. News Digital Object Group , (2021)
9. A phase 2 study of siG12D LODER in combination with chemotherapy in patients with locally advanced pancreatic cancer (PROTACT). CTG Labs- NCBI , (2023)
10. Koga, T., et al. Kras secondary mutations that confer acquired resistance to Kras G12C inhibitors, Sotorasib and Adagrasib, and overcoming strategies: insights from in vitro experiments. Journal of Thoracic Oncology  16 ,1321-1332 (2021)
11. Awad, M. M., et al. Acquired resistance to krasg12c inhibition in cancer. New England Journal of Medicine  384 ,2382-2392 (2021)