Targeting RAC1 signalling to overcome KRAS inhibitor resistance in lung adenocarcinoma

Closing date: 09/03/2026

MB-PhD Studentship: Targeting RAC1 signalling to overcome KRAS inhibitor resistance in lung adenocarcinoma

Lead Supervisors: Prof. Angeliki Malliri
Co-Supervisors:
Dr Colin Lindsay, Dr Martin Baker, Prof. Adam Hurlstone

Applications Deadline: Monday 9th March 2026
Interviews: Week commencing 27th April 2026
Start date: September 2026

Project Keywords: Lung adenocarcinoma, KRAS inhibitors, therapy resistance
Research Opportunity: MB-PhD Studentship

Project Outline

Lung adenocarcinoma is the most common form of non-small cell lung cancer. New precision drugs that directly inhibit mutant KRAS (for example, KRAS-G12C inhibitors) can shrink tumours, but many cancers either do not respond well or soon become resistant. One reason is that cancer cells can adopt a more mobile, treatment-tolerant state called epithelial-to-mesenchymal transition (EMT). This project aims to investigate whether mutant KRAS drives resistance by activating the RAC1 signalling pathway —a key controller of cell movement and EMT and one of the pathways activated downstream of KRAS— and if RAC1 inhibition restores sensitivity to KRAS inhibitors.

The student will explore three linked questions. First, do different KRAS mutations found in lung adenocarcinoma switch on RAC1 to different degrees? Second, which RAC1 “on-switch” proteins (GEFs) are responsible? Third, does blocking RAC1 signalling —genetically or with emerging RAC1-pathway inhibitors—improve responses to KRAS-targeted drugs and help prevent or overcome resistance?

To do this, the student will use engineered airway cell models where specific KRAS mutants can be turned on and off, together with a panel of human lung adenocarcinoma cell lines. Readouts include RAC1 activity assays, quantitative imaging, and standard viability/apoptosis assays to quantify drug response. The project builds on strong pilot data linking EMT, RAC1 activation, and decreased sensitivity to KRAS inhibitors.

The student will be embedded in the Cell Signalling Group (Oglesby Cancer Research Building), with day-to-day guidance from two experienced postdoctoral scientists and a supportive supervisory team that includes clinical and non-clinical expertise. They will gain a broad toolkit in molecular/cell biology, quantitative imaging, and drug-response analysis, present their work at conferences and publish their findings. The ultimate goal is to identify rational combination strategies and biomarkers to inform future clinical studies in KRAS-mutant lung cancer.

Applications for this project are now open. Please complete your application on The University of Manchester Postgraduate Application Portal.

About Prof. Angeliki Malliri (project Lead Supervisor)

Angeliki completed her bachelor’s degree in Biology at the University of Patras and obtained her PhD from the University of Crete, Greece. She worked as a postdoctoral scientist at the CRUK Beatson Institute in Glasgow and the Netherlands Cancer Institute in Amsterdam. She established her independent research group in 2004 at CRUK Manchester Institute and moved to the Division of Cancer Sciences of the University of Manchester in March 2024.

A focus of her laboratory has been the mechanisms controlling and mediating cell migration and invasion, definitive characteristics of malignant cells essential for metastasis. For this, they have been concentrating on Rho-like GTPases and in particular the Rho-like GTPase Rac1 because of its importance in cytoskeletal organization, cell polarity, adhesion and extracellular matrix remodelling required for migration and invasion.

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