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(MCRC Clinical) Investigating resistance to G12C inhibitors in KRAS G12C mutant non-small-cell lung cancer


Project Description

Project summary:
Lung cancer is the leading cause of cancer deaths worldwide, accounting for approximately 20% of cancer mortality. Non-small cell lung cancer (NSCLC) represents 80–85% of all lung cancers, of which a major molecular subset is defined by gain-of-function KRAS mutation (KRASm) in ∼25–35% of newly diagnosed cases. The commonest KRAS mutation detected in NSCLC is G12C. Three different direct KRAS G12C-targeted drugs have entered clinical testing over the past year, with the first evidence for efficacy in lung cancer from these agents considered to be the breakthrough moment of ASCO 2019. Retrospective reports from clinical trials also suggest that KRASm NSCLC is more sensitive to immune checkpoint inhibitors (CPIs) than other mutational subtypes of NSCLC, making future combination strategies of targeted therapy and CPIs particularly appealing in this subgroup.

Through this studentship, we will: i) identify and validate mechanisms of acquired resistance to G12C inhibitors through selection of resistant clones of human NSCLC cell lines carrying the KRAS G12C mutation. We will corroborate these mechanisms in patient samples taken from upcoming clinical trials of KRAS G12C inhibitors at the Christie Hospital; ii) characterise tumourigenesis and the tumour immune micro-environment of KRAS G12C genetically-modified mice that we have recently generated in CRUK MI using CRISPR technology; and iii) examine the efficacy of KRAS G12C inhibition in this G12C mouse model, including characterising changes in the immune infiltrate, and evaluate combination approaches using inhibitors of signalling pathways which co-operate with KRAS signalling and potentially CPI.

Entry Requirements:
Candidates must be post-registration clinicians and ideally have a specialist post in a related subject, for example, obstetrics and gynaecology, oncology, or primary care. Applicants must have been resident and worked within the EEA (European Economic Area) for at least three years prior to application.

Funding Notes

The clinical fellowships are usually tenable for three years, although in certain circumstances they may be four years duration. We will provide running expenses, an appropriate salary in line with the applicant’s current salary and grade, and full coverage of University PhD fees. Where international student fees are payable, please provide evidence with your application of how the shortfall will be covered (approximately £19,000 per annum).

The length of this project will be FOUR YEARS.

Related Subjects

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