Profiling drug-resistant MEN2/MTC RET variants for novel chemical inhibitor sensitivities

Professor Neil McDonald (Francis Crick Institute, London)

Inherited alterations in the RET protein directly cause MEN2 by activating RET, switching on an inappropriate signal in cells leading to cancer. Clinically approved drugs that block RET being activated are now in use as therapies for RET-driven cancers including MEN2/MTC. These drugs, known as tyrosine kinase inhibitors, target a pocket within RET to prevent it functioning. However, the use of tyrosine kinase inhibitors in other cancer contexts has shown that patients eventually relapse and drug-resistant forms of the original cancer appear. This drug resistance arises because the cancer cells mutate to shrug off the effectiveness of the anti-cancer drug, in an analogous process to the development of antibiotic resistance in bacteria.

This proposal will use the tools and insights we have gathered over the past 15 years of working on the RET protein to characterise known and anticipated drug-resistant RET mutations and identify inhibitors that selectively block their activation. Such drugs when combined with the clinically approved drugs, would give a wider set of drugs to tackle MEN2, a second line of defence if/when patient relapse occurs and it would allow more diverse approaches for MEN2 treatment involving drug holidays, where short exposure to varying types of RET inhibitors, reduce the opportunity for drug resistance arising.

More About Professor McDonald

Neil did his doctoral training in protein crystallography with Sir Tom Blundell at Birkbeck College. He was awarded a prestigious Lucille P. Markey Scholarship to move to New York for his postdoctoral training with Professor Wayne A. Hendrikson in the Department of Biochemistry and Molecular Biophysics at Columbia University. He then moved back to London to join the Imperial Cancer Research Fund in London as a group leader in 1994, where he has been ever since. Neil also holds a Chair in Structural Biology at Birkbeck College, a position he has held since 2006. His research interests are focused on the structural biology of growth factor signalling, with a particular interest in the mechanisms of activation and deregulation of the RET receptor tyrosine kinase in human cancer. He has contributed to several CR-UK and Wellcome-funded drug discovery programs, including one that has delivered a first-in-class, pre-clinical candidate against a kinase cancer target.

Neil said, “I am delighted to receive a Research Fund Award from AMEND. The award will allow me to explore drug vulnerabilities of MEN2/MTC RET variants, in particular those variants that are likely to be insensitive to current drug treatments. Our approach could prove crucial to stimulate the search for a second and third generation of improved drugs to treat MEN2 disease and to help benefit patients.”