Grant: Project Grant

RAS is one of the most frequently mutated cancer-causing genes that govern several cellular processes critical for cancer cell survival and growth. Despite intensive efforts since its discovery over three decades ago, drugs directed against RAS have ultimately failed in the clinic, in part due to our incomplete understanding of how RAS is regulated, prompting the widely held perception that RAS is 'undruggable'. Recently, we made a seminal discovery showing that RAS when phosphorylated (a type of modification) is effectively turned 'OFF', while when de-phosphorylated (removal of modification) RAS is turned 'ON'. Armed with this new knowledge, we showed that RAS could be inactivated indirectly by blocking its de-phosphorylation (i.e., activation) process. In this proposal, we will elucidate precisely how these modifications regulate the activity of RAS, which will significantly advance our molecular understanding of this commonly mutated gene in cancer with the supposition that lessons learned will also lay the foundation for the development of novel cancer therapies.