The role of the Integrated Stress Response in tumour cell responses to ERK pathway inhibitors

Academic Supervisor: Simon Cook

Industrial Partner: Cancer Research Technology Limited trading as Cancer Research Horizons

The Babraham Research Campus (BRC) is pleased to announce that it has available a number of studentships from its BBSRC Collaborative Training Partnership (CTP) Award to start in October 2025. The BRC CTP is a joint partnership between the Babraham Institute, the BBSRC and BRC and a range of innovative tenant companies on the Campus working in the Bioscience for Health BBSRC priority area. The goals of the BRC CTP are (i) to train excellent PhD students in the advancing frontiers of bioscience discovery and the Bioscience for an integrated understanding of health priority areas and to provide them with a range of scientific and transferable skills; (ii) to give them ‘real-world’ experience of working in the commercial bioscience sector through their respective collaborative PhD projects and (iii) thereby train the next generation of researchers, skilled in modern techniques, critical thinking and business skills. The distinct features and location of the BRC will provide students with access to real-world examples of translational activity, innovation and entrepreneurship and will lead to future careers in academia, industry and science-based tech transfer and commercialisation.

The Babraham Institute is a world-leader in fundamental biological research investigating the systems that underpin development and healthy ageing. It is a recognised postgraduate University Partner Institute of the University of Cambridge. This BRC CTP Studentship, starting October 2025, will be available leading to a University of Cambridge PhD degree in the laboratory of Dr Simon Cook Simon Cook » Babraham Institute. This studentship is awarded for 4 years.

Details of our interactive scientific programmes can be found on www.babraham.ac.uk. As a student at the Institute, you will have access to all of our outstanding science facilities, each one providing specialist equipment and expertise to support key research techniques and technologies. 

Project Details

Protein kinases are frequently deregulated in human cancer due to mutations, translocations and gene amplifications resulting in dominant activated enzymes that drive phosphorylation to sustain cancer. Inhibitors of these kinases have proved to be an effective therapeutic approach in some cancers including EGFRi in non-small cell lung cancer and BRAFi in melanoma. However, not all tumour cells respond (intrinsic resistance) whilst those that do can adapt, resulting transient clinical responses (acquired resistance).

The Integrated Stress Response (ISR) is an ancient signalling pathway that allows cells to adapt to various forms of stress. Stress-induced activation of one of four eIF2a kinases (EIF2Aks – PERK, GCN2, HRI and PKR) drives phosphorylation eIF2a and attenuation of protein synthesis but allows non-canonical translation of ATF4 to drive a homeostatic gene expression programme, allowing cells to adapt. However, if the ISR is activated too strongly or for too long, it can promote cell death.

Recent studies have shown that an increasing number of protein kinase inhibitors are able to activate the ISR. This may be because tumour cells ‘interpret’ inhibition of their driver kinase as a stress. But in other cases ATP-competitive inhibitors designed to inhibit oncogenic protein kinases bind direct to EIF2Aks and activate them. For example, we have recently shown that a range of RAF inhibitors activate GCN2 to promote ISR activation (1,2)

This raises fundamental questions about the role of the ISR in tumour cells. Does it promote tumour cell survival thereby limiting the efficacy of kinase inhibitors? Or is it desirable, cooperating with kinase inhibitors to kill cells. And what effect might it have on bystander cells that are not addicted to oncogenic kinases?

This project aims to address these questions studying defined human tumour cell lines with known dependencies on specific oncogenic kinases. We will employ standard cell & molecular biology techniques including cell culture (including co-culture), western blot, RNAseq, RNAi, CRISPR, mutagenesis and imaging (including high content microscopy).

Keywords: RAF, ERK, Integrated stress response, Kinase inhibitors

How to Apply

All applications for PhD Studentships at the Babraham Institute need to be made using the University of Cambridge Graduate Application Portal (https://www.postgraduate.study.cam.ac.uk/application-process/applicant-portal-and-self-service-account ) regardless of funding source. Please see the “Applying for a PhD” pages on our website ( https://www.babraham.ac.uk/) for further details of the application process.

We hope to be able to invite short-listed applicants to attend our Institute for a series of interviews shortly after the application deadline. This will give applicants an opportunity to meet their Group Leader and their research group, as well as receiving a tour of our research facilities. Reasonable travel expenses will be paid to those invited.

Students will not be able to take up an award unless they meet all University eligibility criteria and are successful in securing admission to the University. In addition, they will not be able to apply for a visa (if needed) until they hold an unconditional offer from the University.

The deadline for submission of applications via the Graduate Application Portal is 24^th November 2024. Incomplete applications will not be considered.

If you would like more information, or have any questions not answered on our website here ( https://www.babraham.ac.uk/work-and-study/phd-programme/phd-applications ), please contact us: The Graduate Studies Programme Administrator, email [email protected] .

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