UK scientists make major leap towards cracking one of cancer’s biggest targets
Breakthrough Manchester-led research identifies promising new treatment strategy as momentum builds against KRAS-driven cancers
New route to targeting KRAS-driven lung cancer
Manchester scientists have identified a new way to target lung cancer caused by the notorious KRAS mutation, expanding the shortlist of lung cancers treatable with targeted therapies.
Published today in the eminent cancer research journal, Cancer Discovery, the Manchester team collaborated with the US biotech, Revolution Medicines, whose drug daraxonrasib has recently been reported to double survival in the treatment of advanced pancreatic cancer. The research focused on the most commonly altered gene that promotes cancer, KRAS, which is present frequently in lung, pancreatic and colorectal cancers. KRAS is a notorious cell signalling gene that, until recently, had been considered ‘undruggable’ since the 1980s.
A powerful combination approach
The report’s experimental work, driven by team members Dr William McDaid and Dr Helen Adderley, describes that a KRAS subtype, called G13C, is directly targetable with a new KRAS inhibitor, currently known as ‘RMC-8839’. The Manchester team also shows that chemotherapy can be uniquely repurposed to target KRAS G13C, which is highly sensitive to this treatment. The combination of RMC-8839 and chemotherapy was particularly powerful, inducing near complete tumour responses in cancer models with this approach.
Building on progress in precision medicine
Genetic or ‘molecular’ targeting using biological agents has transformed lung cancer care over the past 10-15 years, whereby a highly sophisticated drug development process follows the initial identification of new genetic targets in cancer cells. Applying the same principle, previous drugs such as osimertinib (targeted to the EGFR gene) and lorlatinib (targeted to the ALK gene) have dramatically improved survival for patients affected by these changes. It is anticipated that these breakthrough reports from the Manchester team will therefore lead to a new wave of clinical trials and drug development for KRAS G13C. Although G13C is a rarer subtype of KRAS, lung cancer is so common that the research team expect translational breakthroughs for this population to have the potential to improve the lives of up to 3,000 people in the UK per annum.
What has been particularly exciting about this research is that it started from an observation that we made in the clinic, leading to over five years of scrutiny from multi-disciplinary scientists across academia and industry, all dedicated to the cause of cracking KRAS.
Dr Colin Lindsay
Study lead and Medical Oncologist at The Christie NHS Foundation Trust
From clinic to laboratory breakthrough
Dr Colin Lindsay, translational lead for this work at the University of Manchester and Medical Oncologist at The Christie NHS Foundation Trust, said: “Our examples of genetic drug targets for lung cancer in the past few years highlight that, once we characterise and produce a first drug for these changes, translational progress towards the clinic tends to happen at a rapid pace thereafter. What has been particularly exciting about this research is that it started from an observation that we made in the clinic, leading to over five years of scrutiny from multi-disciplinary scientists across academia and industry, all dedicated to the cause of cracking KRAS.”
The findings of this study add to the growing trend towards precision oncology, where treatments are increasingly tailored to the exact genetic makeup of a patient’s cancer rather than the organ in which it originated.
Professor Angeliki Malliri
Scientific Lead and Professor of Cell Biology at The University of Manchester
Next steps for clinical trials
Angeliki Malliri, scientific lead and Professor of Cell Biology at The University of Manchester, stated “The findings of this study add to the growing trend towards precision oncology, where treatments are increasingly tailored to the exact genetic makeup of a patient’s cancer rather than the organ in which it originated.”
Clinical trials will now be pursued to determine whether the RMC-8839, chemotherapy or their combination can improve survival in patients with KRAS G13C-mutant lung cancer.
