Box 1. A complex question.


Whereas German researchers have uncovered a way to target K-Ras, a team from Texas has shown that a prior approach of disrupting Ras interactions with rho guanine nucleotide exchange factors (ARHGEFs; GEFs) may be more clinically relevant than previously believed.

GEFs such as son of sevenless homolog 1 (SOS1) catalyze the rate-limiting step in Ras activation. They promote the dissociation of GDP so GTP can bind and reactivate Ras. Two groups, one from Roche's Genentech Inc. unit and the other from the Vanderbilt University School of Medicine, independently reported compounds that act via Ras-GDP to disrupt the Ras-SOS1 interface and block Ras activation.

Nevertheless, other researchers had questioned whether blocking the Ras-GDP complex would be an effective therapeutic strategy because oncogenic Ras mutants are locked in a GTP-bound conformation, rendering them constitutively active. The expectation was that these mutants could be insensitive to small molecules that act via the GDP-bound conformation.

Now, John Hancock and Alemayehu Gorfe have shown that this is not exactly the case.9

Hancock is integrative biology and pharmacology chairman and professor at The University of Texas Health Science Center at Houston. Gorfe is assistant professor of integrative biology and pharmacology at the university.

In cells cultured for six hours, the team's inhibitors of Ras-GDP did not block oncogenic Ras signaling. However, when incubation periods were prolonged to three days, the compounds decreased oncogenic Ras signaling and oncogenic K-Ras-driven proliferation of multiple cancer cell lines compared with vehicle.

According to Hancock, these prolonged assays demonstrate that "GTP turnover is slow-not absent-so exchange activity is still inhibited. Therefore, this study shows that blocking exchange factor interaction is a viable approach to inhibiting oncogenic mutant Ras function."

The research was published in the Proceedings of the National Academy of Sciences. The team also included scientists from the University of Putra Malaysia.

Hancock said, "It is very hard to predict which of the different approaches to inhibit Ras will be most successful. Inhibiting Ras at multiple levels will likely be the way to go. As we have learned from kinase inhibitors, we need to use two, possibly three drugs to achieve maximal inhibition at the lowest levels of toxicity."

Hancock and Gorfe declined to disclose the patent and licensing status of their work.      -AD