Deep profiling of non-small cell lung cancer clinical samples to identify and validate novel mechanisms of resistance to KRAS inhibition
Closing date: 17/11/2025
Clinical Research Training Fellowship: Deep profiling of non-small cell lung cancer clinical samples to identify and validate novel mechanisms of resistance to KRAS inhibition
Lead Supervisors: Dr Colin Lindsay
Co-Supervisors: Prof. David Wedge, Prof. Angeliki Malliri, Dr Kathryn Simpson, Dr Jamie Weaver
Applications Deadline: 12:00pm Monday 17th November 2025
Interviews: Week commencing 12th January 2026
Start date: September 2026
Project Keywords: RAS, KRAS, NSCLC
Research Opportunity: Clinical Research Training Fellowship leading to the award of PhD
Project Outline
Despite a vast number of studies investigating clinical resistance to KRAS G12C inhibitors, mechanisms of acquired resistance have only been identified in ~25% of NSCLC patients. Nearly all resistance studies have been limited to targeted sequencing on scant diagnostic or plasma samples, so there remains an important need for deeper profiling of tissue samples, as well as patient-derived models, for identifying and characterising resistance to KRAS inhibition.
Aims:
The student will:
1. Access a unique cohort of samples from our ‘RAS-BIO’ biobank, analysing RNAseq and whole exome sequencing from 65 patients treated with KRAS inhibitors, and aiming to identify novel mutational and/or ‘non-genetic’ adaptive resistance mechanisms. Putative mechanisms will be mechanistically validated using an inhouse panel of KRASG12C inhibitor-resistant cell lines. Therapeutic vulnerability for each novel resistance mechanism will be explored.
2. Analyse samples from 3-5 patients with KRAS inhibitor resistance recruited to the Manchester rapid autopsy programme. Patient lesions will be selected according to their representation of differential response between lesions within the same patient, then whole exome profiling will identify novel clones/subclones specifically associated with resistance. Digital PCR will assess if these changes could have been detected in diagnostic tissue samples.
3. Functionally assess two paired patient-derived xenograft (PDX) models, derived from biopsies taken before and after resistance to KRAS inhibition in one patient. The student will analyse differential expression profiling from these PDXs at baseline and at day 7-10 after treatment, with results aligned to their twin PDX. Mechanisms will be validated directly from autopsy samples.
The endpoint of these analyses will be identification, characterisation and validation of novel clones, subclones or pathways critical for driving KRAS inhibitor resistance. The student will ultimately offer novel insights on KRAS inhibitor resistance timing and mechanisms, identifying new combination partners and postulating when to use them in patient care.
Applications for this project are now open. Please complete your application on The University of Manchester website.
About Dr Colin Lindsay (project Lead Supervisor)
Dr. Colin Lindsay, a Clinical Senior Lecturer in Medical Oncology at the Christie NHS Foundation Trust, adeptly manages a dual focus on groundbreaking research and compassionate patient care. His academic journey commenced at the CRUK Beatson Institute in Glasgow, where he earned a PhD under the guidance of Owen Sansom. During this period, Dr. Lindsay delved into the exploration of genetically modified mouse models of RAS and RAF-driven melanoma.
Key information
Before submitting an application, please ensure you have read the information below about the funding arrangements and eligibility for our Clinical Research Training Fellowships.
We also encourage you to get in contact with the lead supervisor to discuss the project and any particulars.
Further information is available on the Clinical Research Training Fellowships webpage.
The clinical fellowships are usually tenable for three years, although in certain circumstances they may be four years duration. The Fellowship covers:
- running expenses,
- an appropriate salary in line with the applicant’s current salary and grade
- full coverage of University PhD fees at the UK/home fee rate.
International Candidates
The University of Manchester aims to support the most outstanding applicants from outside the UK.
We are able to offer a limited number of bursaries to high-performing EU and international candidates, covering PhD fees only. Bursaries do not include financial support for visa/health surcharges.
We assess each EU and international candidate’s suitability for a bursary at the application and interview stages.
You must be a post-registration clinician, and ideally have a specialist post in a related subject, to apply for our Clinical Research Training Fellowships.
Applicants must hold an MBChB degree or an equivalent medical qualification. You should also hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage.
It is generally expected that CRTFs will return to a training programme in the UK upon completion of their research degree.
International applicants (including EU nationals) must ensure they meet the academic eligibility criteria (including English Language) before contacting potential supervisors to express an interest in their project. Eligibility information can be found on the University’s Country Specific information page.
Applications for this programme are now open. Please submit your application on The University of Manchester application portal.
Key dates
- Applications open: Monday 6th October 2025
- Application deadline:12:00pm Monday 17th November 2025
- Interviews:Week commencing 12th January 2026
- Start date: September 2026
Useful Links
Submit your application
Interested in applying for this opportunity? Submit your application on The University of Manchester application portal.
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