Developing a New Chemotherapeutic Strategy for RAS-Induced Cancer

Seth Nickerson, Staff Writer

Life and cancer are two sides of the same coin, separated by the balance between growth and death of an organism’s cells. This equilibrium is maintained by genetic instructions encoded in the DNA of the genome. During a lifespan, one’s DNA is continually modified and mutated in ways that make us who we are, but can also destroy this important cellular balance. In cancer, genetic components of the intricate molecular machines that regulate cell growth and death are mutated, the balance breaks down, and abnormal growth prevails.

Mutations in a gene called Rat Sarcoma (RAS), are found in more than 30% of all human tumors.[1] There are three RAS genes (H-RAS, K-RAS, and N-RAS), and each encodes information to synthesize a protein enzyme that regulates the proliferation and survival of cells. Within the cell, the RAS enzyme is a molecular switch that turns ‘on’ in response to hormones and then automatically shuts ‘off’. This on-off pulse results in a burst of activity that can cause the cell to divide into two daughter cells. If one of the three RAS genes becomes mutated such that RAS enzyme is stuck ‘on‘, then the machine will no longer respond properly to hormones, and the cell will divide continually. The mutant RAS gene is now an oncogene; it promotes the formation of a tumor, which can eventually lead to cancer. [2]

Cells that acquire the oncogenic RAS mutation begin to multiply more frequently. Their rapid growth causes the accumulation of additional mutations, detected as the genetic signature in the resulting tumor. In healthy cells, DNA mutations are acknowledged and repaired, but oncogenic RAS forces the cell to divide without making repairs. Mutations in genes that further promote and support the growth of a tumor will be inherently favored; eventually the genetic signature of full-blown cancer will emerge.

Oncogenic RAS can induce the recruitment and growth of blood vessels to supply the oxygen and nutrient demands of the burgeoning tumor. It can also empower the cancer cells to out-maneuver both the innate and adaptive immune systems. Once the tumor has been established, oncogenic RAS can promote metastasis by enhancing cell migration and invasion. These sweeping changes to cellular physiology contribute to the aggressive properties of oncogenic RAS-driven cancers.

Given the central role of oncogenic RAS in carcinogenesis, tumor development, and cancer progression, inhibition of RAS activity is an attractive drug target for cancer therapy. However, decades of research have shown that RAS activity is not amenable to conventional chemotherapeutic approaches, and therefore, it remains an elusive target.

Our knowledge of the molecular mechanisms governing RAS activation is comprehensive and highlights contrasts between the normal, non- mutated RAS and the oncogenic, mutated version. For instance, normal RAS is switched ‘on’ by its activator Son of sevenless (SOS), and subsequently switched ‘off’ by its deactivator, GTPase activating protein (GAP) (fig.1). [3,4]Upon oncogenic mutation of the RAS gene, the RAS protein it encodes can no longer interact with, and be deactivated by, the GAP. This results in RAS protein that is virtually always switched ‘on’.

It was formerly believed that oncogenic RAS had gone rogue, but recent experimental evidence suggests that it still depends critically on its characteristic cellular counterparts.[5,6] In order to promote cancer, oncogenic RAS still requires activation by SOS.[7] If RAS and SOS were unable to interact, however, oncogenic RAS would become impotent. Therefore, blocking the interaction of RAS and SOS could prevent the effects of the oncogenic RAS mutation.

My research at the NYU School of Medicine is dedicated to developing an inhibitor of the RAS-SOS interaction. It began with the atomic scale molecular structure of RAS and SOS bound together. With the most detailed view of how RAS and SOS interact, we used logic and computational biology to design chemicals that bind to RAS and potentially disable its ability to interact with SOS. The interface between these molecules is vast and complex, and our simulations concluded that no small chemical would be sophisticated enough to interfere between RAS and SOS.

We hypothesized that a decoy protein could mimic SOS and compete for binding to RAS. (fig. 2a) In order to generate a molecule with this functionality, we isolated a critical portion of SOS protein that is responsible for the RAS-SOS interaction and synthesized this particular portion as a stand-alone peptide. This decoy drug imitates SOS because it can bind to RAS, but it lacks the ability to switch RAS ‘on.’ (fig. 2b)

Our experiments began with examining the effects of the SOS decoy drug on the RAS-SOS interaction with purified proteins in a laboratory test. Our decoy drug inhibits the interaction well in a test tube, but it quickly becomes degraded by cell metabolism before it can have a substantial affect. To increase the biological half-life, we reengineered the chemical structure making it resistant to degradation. Eventually, we developed a small protein that can inhibit the RAS-SOS interaction and block the activation of RAS in cancer cells. The SOS decoy is now being tested for its ability to actually kill tumor cells. Our decoy approach is also showing great potential as a means for targeting a spectrum of other protein-protein interactions involved in disease.

Pharmaceutical drug development continues to draw inspiration for successful strategies from natural phenomenon. Successive rounds of improvement of the drug candidates can transform a chalkboard idea into a promising candidate. However, even when excellent new drugs succeed in multiple laboratory experiments, most fail miserably during clinical trial testing. We must wait and see whether our approach will prevail or be shelved like so many drugs before it. Going forward, the molecular decoy concept will remain a serious drug-development approach adaptable to many diseases, including many cancers and genetic disorders.
[1] P. Blume-Jensen, T. Hunter, Oncogenic kinase signalling, Nature 411 (2001) 355–365.

[2] Y. Pylayeva-Gupta, E. Grabocka, D. Bar-Sagi, RAS oncogenes: weaving a tumorigenic web, Nat. Rev. Cancer 11 (2011) 761–774.

[3] P.A. Boriack-Sjodin, S.M. Margarit, D. Bar-Sagi, J. Kuriyan, The structural basis of the activation of RAS by SOS, Nature 394 (1998) 337–343.

[4] J.B. Gibbs, M.D. Schaber, W.J. Allard, I.S. Sigal, E.M. Scolnick, Purification of RAS GTPase activating protein from bovine brain, Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 5026–5030.

[5] A. Young, D. Lou, F. McCormick, Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling, Cancer Discov. 3 (2013) 112–123.

[6] H.J. Hocker, K.J. Cho, C.Y. Chen, N. Rambahal, S.R. Sagineedu, K. Shaari, J. Stanslas, J.F. Hancock, A.A. Gorfe, Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function, Proc. Natl. Acad. Sci. U.S.A. 110 (2013) 10201–10206.

[7] H.H. Jeng, L.J. Taylor, D. Bar-Sagi, SOS-mediated cross-activation of wild-type RAS by oncogenic RAS is essential for tumorigenesis, Nat. Commun. 3 (2012) 1168.

Seth Nickerson is a PhD candidate in the department of Biochemistry and Molecular Pharmacology at the NYU School of Medicine. Contact him at:


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