Unmasking mechanisms of resistance to KRAS inhibition across pancreatic cancer genetic profiles
University of Cambridge, Cancer Research UK Cambridge Institute
Dr Giulia Biffi
Deadline: Friday, October 16, 2026
Competition Funded PhD Project (Students Worldwide)
Cambridge, United Kingdom
Biochemistry | Bioinformatics | Cancer Biology | Cell Biology | Genomics | Immunology | Molecular Biology
About the Project
PhD studentship: Unmasking mechanisms of resistance to KRAS inhibition across pancreatic cancer genetic profiles
Reference: SW51012
Supervisor: Dr Giulia Biffi
Department/location: Cancer Research UK Cambridge Institute
Deadline for application: 16th October 2026
Course start date: 1st October 2027
Overview
Dr Giulia Biffi wishes to recruit a student to work on the project entitled: “Unmasking mechanisms of resistance to KRAS inhibition across pancreatic cancer genetic profiles”.
For further information about the research group, including their most recent publications, please visit their website at https://biffilab.wordpress.com
This is a unique opportunity for PhD study in the world-leading Cancer Research UK Cambridge Institute (CRUK CI), to start a research career in an environment committed to training outstanding cancer research scientists of the future.
If you are interested in finding out more about our groundbreaking scientific research, please visit our website at https://www.cruk.cam.ac.uk/
Project details
Pancreatic ductal adenocarcinoma (PDAC) remains a formidable clinical challenge, largely because most patients present with advanced or metastatic disease and current treatments have limited efficacy in this setting. A major recent advance has been the development of KRAS inhibitors, which have shown considerable promise in clinical trials (1). KRAS mutations are present in more than 90% of PDAC tumours and are key drivers of disease initiation and progression. 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. Most mechanistic pre-clinical studies of therapy response have relied on mouse models driven by KRAS and p53 mutations alone. This is important because human PDAC is genetically heterogeneous, with additional alterations that vary not only between patients but also within individual tumours, yet this complexity is often not captured in commonly used pre-clinical models.
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 [(2) and unpublished]. 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 (3, 4). 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.
References/further reading
- Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. N Engl J Med. 2026. (PMID: 42223072)
- SMAD4 and KRAS status shape malignant-stromal crosstalk in pancreatic cancer. Cancer Res. 2025. (PMID: 39841099)
- EGFR-activated myofibroblasts promote metastasis of pancreatic cancer. Cancer Cell. 2024. (PMID: 38157863)
- Functional heterogeneity of fibroblasts in primary tumours and metastases. Trends in Cancer. 2024. (PMID: 39674792)
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.
Funding
This four-year studentship is funded by Cancer Research UK Cambridge Institute and includes full funding for University fees, with an index-linked stipend starting at £22,894pa for four years in 2027-28.
Eligibility
We welcome applications from both UK and overseas students.
Applications are invited from recent graduates or final-year undergraduates who hold or expect to gain a First/Upper Second Class degree (or equivalent) in a relevant subject from any recognised university worldwide.
Applicants with relevant research experience, gained through Master’s study or while working in a laboratory, are strongly encouraged to apply.
How to apply
Please apply via the University Applicant Portal. For further information about the course and to access the Applicant Portal, visit: https://www.postgraduate.study.cam.ac.uk/courses/directory/cvcrpdmsc
You should select to commence study in October 2027.
Additional information
To complete your online application, you will need to answer/provide the following:
Choice of project and supervisor
Please ensure that you name the project (with reference code) and supervisor, where indicated. You are permitted to apply for up to three projects.
Course-specific questions
- You will be asked to give details of your Research Experience (up to 2,500 characters)
- Your Statement of Interest (up to 2,500 characters) should explain why you wish to be considered for the studentship and what qualities and experience you will bring to the role.
Supporting documents
Applicants will be asked to provide:
- Academic transcripts
- Evidence of competence in English (if appropriate)
- Details of two academic referees
- CV/resume
References
We would appreciate it if you could ask your referees to submit their references as soon as possible upon request, despite the longer University deadline for references. They will receive a request once you have completed the References section of your application.
Deadline
The closing date for applications is 16th October 2026, with interviews expected to take place in the week beginning 4th January 2027.
Funding Notes
This four-year studentship is funded by Cancer Research UK Cambridge Institute and includes full funding for University fees, with an index-linked stipend starting at £22,894pa for four years in 2027-28.
References
- Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer. N Engl J Med. 2026. (PMID: 42223072)
- SMAD4 and KRAS status shape malignant-stromal crosstalk in pancreatic cancer. Cancer Res. 2025. (PMID: 39841099)
- EGFR-activated myofibroblasts promote metastasis of pancreatic cancer. Cancer Cell. 2024. (PMID: 38157863)
- Functional heterogeneity of fibroblasts in primary tumours and metastases. Trends in Cancer. 2024. (PMID: 39674792)
This is a Preview Listing…
You must sign in to see the full job description, and to apply.
Manage / Upgrade this job to a Full Job Listing.
Find Your Best Opportunity
Tell them AcademicJobs.com sent you!