Targeting Mutant FBXW7 to Disable MCL1 and Induce Therapeutic Apoptosis

Precision medicine strategies are lacking for patients with mesothelioma, a cancer of lining the lung. It is caused by exposure to asbestos and is universally lethal. The UK has the highest rate of mesothelioma diagnosis in the world. Ongoing mining of asbestos is set to create epidemics worldwide, particularly in developing nations, based on import statistics.

Recent insights into the mutational landscape of mesothelioma and in particular the genomic evolution of this cancer, has revealed inactivation of the E3 ubiquitin ligase and tumour suppressor FBXW7 localised on chromosome 4, as an early clonal event. FBXW7 controls the stability of the prosurvival BCL2 family protein MCL1 by facilitating its rapid degradation. Conversely, somatic inactivation of FBXW7, blocks MCL1 degradation leading to its constitutive upregulation, and suppression of mitochondrial apoptosis. This translates into marked drug resistance, and poor survival in patients with mesothelioma. It is predicted that targeting of MCL1in FBXW7 mutant mesothelioma, either through pharmacologically mediated transcriptional suppression or accelerated degradation may confer selective toxicity to FBXW7 mutated mesothelioma, thus opening up a tractable translational strategy to treat this group of patients and improve survival outcomes.

Entry requirements

UK Bachelor’s Degree with at least 2:1 in a relevant subject or overseas equivalent. 

University of Leicester English language requirements apply where applicable.

Informal enquiries

Professor Dean A. Fennell  [Email Address Removed]

To apply, please follow the guidance at:

https://le.ac.uk/study/research-degrees/funded-opportunities/lpmi-fennell-2021