PhD Studentship: Unmasking mechanisms of resistance to KRAS inhibition across pancreatic cancer genetic profiles in Cambridge

Supervisor: Dr Giulia Biffi

Course start date: 1st October 2027

Project details:

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge. A major recent advance has been the development of KRAS inhibitors, which have shown considerable promise in clinical trials. For decades, KRAS was considered undruggable; however, these new inhibitors represent a potential turning point for patients with PDAC. Despite this progress, rapid therapy resistance has already been observed in both patients and pre-clinical mouse models, highlighting the urgent need to define the mechanisms that drive resistance and to identify rational combination therapies.

In our laboratory, we have established and validated a panel of genetically heterogeneous PDAC models. These studies have shown that malignant-cell genetics shape distinct, therapeutically actionable vulnerabilities through both cell-intrinsic programmes and changes in the surrounding tumour microenvironment. These observations create an important opportunity: we hypothesise that malignant-stromal crosstalk within defined genetic contexts drives distinct mechanisms of resistance to KRAS inhibition. In support of this, our work indicates that cancer-associated fibroblasts play diverse roles in PDAC progression and activate pathways that may contribute to therapy resistance.

This PhD project will therefore identify malignant cell-intrinsic and malignant cell-extrinsic mechanisms of resistance to KRAS inhibition, including fibroblast-mediated mechanisms, across genetically distinct PDACs. We will prioritise PDAC genotypes for which we already have preliminary data suggesting candidate mechanisms of resistance. The project will combine complementary models and techniques, including co-transplantation of organoids in mouse models, in vivo CRISPR, single-cell RNA sequencing, flow cytometry, multiplex immunofluorescence, spatial transcriptomics, and standard molecular biology approaches. A computational component may also be available, depending on the skills and interests of the student. Together, these strategies will define how intra-tumour genetic heterogeneity influences response and resistance to KRAS inhibition, complementing ongoing studies in the laboratory investigating inter-tumour genetic heterogeneity.

Preferred skills/knowledge:

• We are looking for a motivated student who is excited by this project, enthusiastic about joining a collaborative and hard-working laboratory, and committed to the complementary experimental strategies required for its successful completion.
• As this project will rely heavily on mouse models, willingness to work with mouse models throughout the PhD is essential.
• Prior experience in a laboratory or industry research environment is required.
• Experience with tissue culture, including cell lines and/or organoids, common laboratory techniques such as immunohistochemistry, western blotting and/or PCR, and work with mouse models would be viewed favourably.
• Prior experience or knowledge of pancreatic cancer or cancer biology would also be advantageous.

Eligibility:

We welcome applications from both UK and overseas students. The University actively supports equality, diversity and inclusion and encourages applications from all sections of society. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.