RAS Research
The RAS gene family, comprising three isoforms or subtypes (KRAS, HRAS and NRAS), represents the most frequently mutated driver gene in human tumours, occurring in up to 30% of all cancers. Among these, KRAS is the most commonly mutated cancer driver gene, present in approximately 86% of RAS-mutant cancers and very commonly contributing to difficult-to-treat cancers such as pancreas and colorectal carcinomas.
In lung cancer, KRAS mutations are observed in up to one-third of cases, making it one of the most prevalent genetic alterations in this cancer type which easily remains the biggest cause of tumour mortality. A specific type of KRAS mutation called KRAS G12C is the most common mutation in lung cancer, affecting ~13% of patients.
RAS mutations
RAS mutations play a key role in lung cancer growth, by altering genes that regulate cell growth, thus causing uncontrolled abnormal cell growth, and aggressive tumour formation. Understanding the mechanisms of RAS mutations is crucial for developing targeted therapies and enhancing treatment approaches.
RAS mutations refer to changes in the genetic code of the RAS genes, a family of genes crucial for regulating cell growth and division. These mutations can result in the production of altered RAS proteins, disrupting the normal control mechanisms that dictate when cells should grow and divide. In the context of lung cancer, RAS mutations are known to play a central role in the disease’s progression. The faulty RAS proteins encourage the uncontrolled proliferation of cancer cells, contributing to the formation of aggressive tumours.
Understanding the intricate details of RAS mutations is essential as it paves the way for developing targeted therapies. By specifically addressing the effects of RAS mutations, researchers aim to enhance the effectiveness of treatments and improve overall outcomes for individuals dealing with lung cancer.
RAS Research in Manchester
In Manchester, our researchers are leading on research spanning non-clinical and clinical research involving the RAS gene.
The RAS Lab, led by Dr Colin Lindsay, explores the complexities of lung cancer and aims to develop practical solutions. The lab group focuses on understanding RAS mutations in lung cancer with a goal of advancing the field of lung cancer treatment with effective, personalised therapies. Specifically, the RAS lab aims to:
- Delve into the mechanisms behind RAS mutations
- Develop targeted therapies to combat these mutations and improve treatment outcomes
- Translate laboratory findings into tangible improvements in lung cancer prevention, early detection, and treatment.
Manchester also benefits from its partnership with Cancer Research UK and University College London (UCL) in the Lung Cancer Centre of Excellence, combining UCL’s immune system research and genetics exploration with Manchester’s strengths in radiotherapy, drug discovery, and biomarker identification. The overarching goal of the Centre is to enhance knowledge in genetics, biology, and tumour adaptation for improved prevention, diagnosis, treatment, and care, ultimately elevating outcomes for lung cancer patients. Its establishment marked a significant step in advancing global leadership in lung cancer research.
Ongoing Projects
CodeBreak-200
The CodeBreak-200 trial, led by Dr. Colin Lindsay and the Manchester RAS Lab team, marked a significant leap forward in the treatment of RAS-mutated cancers, particularly advanced lung cancers with the KRAS G12C mutation. RAS, a challenging gene for drug development due to its unique properties, saw a breakthrough a decade ago when a pocket within the RAS protein was discovered. This discovery paved the way for the development of sotorasib, a precision medicine that targeted the KRAS G12C mutation.
In a phase III clinical trial, sotorasib demonstrated its superiority over the standard chemotherapy, docetaxel, in treating advanced lung cancers with the KRAS G12C mutation. The trial showcased sotorasib’s effectiveness, faster action, and better quality of life for patients. Dr. Colin Lindsay, consultant medical oncologist at The Christie, and leader of the MCR RAS Lab team, emphasized the global impact of this breakthrough, stating that it was a game-changer for the treatment of RAS mutation and stage 4 lung cancer.
Sotorasib, an orally administered drug, offered patients the convenience of at-home treatment, improved tolerance, and enhanced efficacy compared to traditional chemotherapy. The study, funded by Amgen, a leading biotechnology company in the US, revealed that after 12 months, 25% of patients on sotorasib experienced no cancer growth, compared to only 10% in the chemotherapy group.
This breakthrough not only led to the adoption of sotorasib as a new standard in RAS precision medicine but also spurred global clinical trials exploring similar drugs. The development of RAS inhibitors emerged as a promising avenue in cancer treatment, benefiting a substantial number of patients and providing a model for addressing other RAS mutations. The CodeBreak-200 study, conducted at the NIHR Manchester Clinical Research Facility, brought hope for a brighter future in precision medicine for cancer.
TRACERx
The RAS lab actively participated in the Lung TRACERx (TRAcking Cancer Evolution through therapy Rx) project, led by Professor Charles Swanton at University College London. This prospective observational cohort study, funded by Cancer Research UK, aimed to transform our understanding of non-small cell lung cancer (NSCLC) through comprehensive translational research. Over a nine-year period, involving 842 patients from diverse UK hospitals, the study investigated intratumor heterogeneity and its implications for patient stratification, leading to the development of innovative targeted and immune-based therapies. The trial has provided valuable insights and contributions to the field of lung cancer research.
Meet the team
Dr Colin Lindsay
Clinical Senior Lecturer in Medical Oncology
Jack Webster
Translational Research Facilitator
Mathew Carter
Senior Translational Research Facilitator
Charlotte Hindley
Translational Research Facilitator
Dr Kate Brown
Translational Research Manager
Dr Laura Woodhouse
Clinical Research Training Fellow
Dr George Morrissey
Clinical Research Training Fellow
Dr Helen Adderley
Clinical Fellow
Angeliki Malliri
Professor of Cell Biology
Where RAS research is performed
Researchers focused on RAS research operate from the following facilities across Manchester:
Banner image: Hyperion IMC (imaging mass cytometry) subcellular imaging courtesy of Dr Laura Woodhouse in collaboration with Couper Lab, University of Manchester.
The basic biology of lung cancer with Dr Colin Lindsay: Exploring oncogenic drivers such as the KRAS mutation
