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Ras Genes in Health and Disease

Final Report Summary - RAS AHEAD (Ras Genes in Health and Disease)

RAS proteins are essential mitogenic switches. They are responsible for allowing the transfer of external signals from outside of the cell to the nucleus. We can think of RAS proteins as those switches that allow us to turn lights on and off. Unfortunately, these switches often “break down” and cannot be turned off, thus forcing us to leave the lights on. In biological terms, RAS proteins cannot be switched off when they are mutated and become oncoproteins, that is “cancer-causing” proteins. Cells expressing mutant RAS proteins “believe” that they are continuously receiving instructions to proliferate, a situation that in the appropiate context, can lead to the generation of malignant tumors. Indeed, as many as one fifth of all human tumors carry mutations in one of the three members of the RAS family, mainly in K-RAS. K-RAS mutations are associated with three of the worse human cancers, adenocarcinomas of the lung, colon and pancreas. Sadly, these tumors are still treated with non-selective cytotoxic drugs brought to the clinic more than 20 years ago. As a consequence, the survival rate for these patients remains below 20%. Why don’t we have effective medicines to treat these tumors?. First of all, K-RAS is not a druggable protein. That is, the scientific community has not been able to figure out as yet, how to design drugs to block mutant K-RAS. Ironically, many K-RAS effectors, that is, those molecules responsible for mediating its malignant properties, are kinases, a type of protein for which it is possible to design selective inhibitors. Unfortunately, some of these kinases are essential for normal homeostasis, so we cannot block them without causing severe toxic effects. The challenge is to identify kinases (or other druggable effectors) that while necessary for tumor development are dispensable for normal tissues, one of the key issues addressed in this project.
Overall, the RAS AHEAD proposal focused on understanding how RAS proteins signal in health and in disease using animal models. For instance, we have developed strains of mice in which we can eliminate the three members of the RAS family to interrogate their role in adult homeostasis. We have observed that concomitant elimination of the three RAS proteins causes rapid wasting in most tissues leading to the dead of mice in less than two weeks. These results underscore the importance that RAS proteins have in normal physiology and the difficulty in tampering with them without causing damage to our healthy tissues. We have also developed animal models for certain RASopathies, a series of developmental diseases, such as Costello or Noonan syndromes, caused by non-oncogenic RAS mutations that result in the partial activation of these proteins. These mouse models faithfully reproduce the developmental defects observed in human patients and will be highly instrumental to test the efficacy and safety of forthcoming drugs selective for these altered RAS proteins. The third aim of this proposal focused on the identification of targets with therapeutic value for K-RAS driven cancers, mainly pancreatic and lung tumors. We have determined that the MEK and ERK kinases are absolutely essential for life, thus representing unsuitable targets. Indeed, those MEK inhibitors that have already reached the clinic have proven to be highly toxic, as predicted by our studies. Fortunately, we have identified three selective targets essential for tumor development but not for normal homeostasis, one of the key challenges mentioned above. Two of them, the Cdk4 and c-Raf kinases are effective against lung tumors whereas c-Raf and the EGF Receptor play a key role in the development of pancreatic tumors. Thanks to these studies, several drugs such as Palbociclib and Abemaciclib are being tested in clinical trials with promising results. Combination studies suggest that Cdk4 and c-Raf inhibitors will have a significant effect in the treatment of lung cancer patients. Thus, our studies supported by the RAS AHEAD Advanced Grant have not only help to get a much better understanding on how RAS proteins signal in heath and disease, but have also opened the door to the discovery of selective medicines that will improve the way lung and pancreatic cancer patients will be treated in the forthcoming future.