Work in which the team of Xosé Bustelo, from the Cancer Research Center (CSIC-USAL) of Salamanca, has participated
CIBER/DICYT An international research team has discovered the reason for the failure of a family of antitumor compounds, originally conceived as highly promising. The study published in Science Advances was led by Piero Crespo, CIBERONC group leader at the Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC), and Berta Casar, from the same team; in collaboration with the Xosé Bustelo group, head of the CIBERONC group at the Cancer Research Center (CIC, mixed center of the CSIC and the University of Salamanca). The University of Edinburgh (United Kingdom) and the National Institutes of Health (NIH) USA have also participated.
Approximately 30% of human tumors carry mutations in some component of the RAS-ERK biochemical pathway. This route is made up of four proteins: RAS, RAF, MEK and ERK, which activate one another, sequentially and successively, coupling a transmission chain through which the necessary mechanisms for cell proliferation are put into operation. In tumor cells, mutations in any of these proteins cause said transmission chain to be aberrantly activated, constantly, so that the cells proliferate uncontrollably. The importance of this pathway in carcinogenesis is such that, in the last 25 years, large pharmaceutical companies have invested billions of dollars in designing compounds through which uncontrolled signaling through it can be stopped. As a result of this effort, today the components of this pathway constitute promising molecular targets towards which various antitumor drugs are directed, successfully used in the clinic for the treatment of tumors such as lung cancer, colorectal cancer and melanoma.
The transmission of signals through the RAS-ERK pathway is optimized through the participation of “framework proteins”, in charge of assembling the four components properly. A few decades ago it was discovered that mice deficient in one of these proteins, called KSR, were extremely resistant to developing tumors, raising the hypothesis that inhibiting KSR activity could be a valid strategy as antitumor therapy. In this sense, in 2015 a molecule appeared, APS 2-79, which blocked the activity of KSR at the level of its interaction with MEK. However, its antitumor effect was very disappointing, so its clinical development was not continued.
At work published in Science Advances, Drs. Crespo and Casar reveal the reason for this failure: there are several types of framework proteins in cells, and in tumor cells, one of these, called IQGAP1, binds to KSR. Due to this interaction, MEK bound to IQGAP1 can activate ERK bound to KSR. IQGAP1 thus serves as a molecular “bridge” through which the inhibitory effect of APS 2-79 is avoided. “In this way, IQGAP1 would act as a splice, restoring the signal flow through KSR” according to the researchers. In accordance with this, Drs. Crespo and Casar have shown that in melanoma cells devoid of IQGAP1, the antitumor effect of APS 2-79 is greatly increased.
“KSR continues to be a very promising therapeutic target”, the researchers argue, “the reason for the failure of APS 2-79 is that its mechanism of action is not adequate, to effectively block the activity of KSR, it is necessary to prevent its interaction with ERK, this is the only way to avoid ‘molecular splicing’ processes such as those described”. In this sense, Drs. Crespo and Casar are already looking for such types of inhibitors.
