MICA: Un-jamming the Ras switch - blocking Ras nucleotide exchange and promoting GTP hydrolysis

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A protein called Ras has, for many years, been an extremely important therapeutic target in many types of cancers, yet the ability to target Ras with drugs is still elusive. Under normal conditions Ras acts as a switch that turns on and off, regulating major cellular processes such as growth, division and migration. In a high proportion of cancers the Ras switch is broken and remains in a 'on' state causing uncontrolled cellular growth. This process is often a result of Ras mutations causing the protein to avoid the normal regulatory mechanisms which usually turn it off or regulate it being on in the first place. As part of an Innovate feasability grant in collaboration with a company (Tecrea) our group generated reagents, termed Affimers, that blocked Ras function. Interestingly the reagents can either block Ras from being turned on in the first place or specifically target mutant Ras and turn it off. This represents a very exciting development in understanding the ability to specifically target mutant Ras proteins and could aid the design of drugs to mimic the Affimers or be used as drugs per se. However, the aim of this proposal is to determine how the Affimers are inhibiting Ras function, to try improve on this ability by modifying the Affimers and test their ability to modulate Ras function in cells.