Defining how reactive small molecules in cells regulate the oncogenic KRAS.G12C GTPase

PhD Start date: September 2020

The KRAS gene are among the most mutated genes in cancer cells. KRAS.G12C (glycine at position 12 to cysteine), which is found in about 12% of all KRAS-mutated cancers, has attracted much attention as the cysteine residue is highly reactive. Being nucleophilic and redox-sensitive, it can react with electrophiles and oxidants – this reactivity is exploited to develop KRAS.G12C-selective inhibitors. However, reactions between KRAS.G12C and endogenous electrophiles have not been reported.

One of the major environmental factors that affect electrophiles in tissues and cells is smoking, which has a proven correlation with lung cancer occurrence. Interestingly, in KRAS-mutated lung cancer samples, G12C incidence is as high as over 40%.

This interdisciplinary project in the Tanaka and Hopkinson groups will assess whether KRAS.G12C reacts with cellular electrophiles/oxidants and whether these reactions affect KRAS biology. Ultimately, these studies will help to define how KRAS.G12C induces cancer and will lead to novel chemotherapies.

Academic entry requirements:
UK Bachelor Degree with at least 2:1 in a relevant subject or overseas equivalent.

How to apply:
Standard application: https://le.ac.uk/study/research-degrees/funded-opportunities/cls-mcb-liscb-2020

Eligibility:
UK and EU candidates only