Breakthrough research led by scientists in Manchester has identified a new drug combination that could improve outcomes for thousands of patients with lung cancer driven by a rare type of KRAS mutation, offering hope for patients worldwide with this difficult-to-treat subtype of lung cancer.
A study published in Cancer Discovery, focuses on non-small cell lung cancer (NSCLC) which accounts for around 20% of cancer-related deaths worldwide. Mutations in the KRAS gene are one of the most common causes of NSCLC. The findings reveal that a subgroup of KRAS mutations known as KRAS codon 13 mutations, including KRAS G13C, behave differently from more common KRAS mutations such as KRAS G12C, creating an opportunity for a new precision medicine approach which is particularly effective.
Historically, researchers and oncologists could not effectively target KRAS mutations to treat NSCLC. While major advances have been made for the more common KRAS G12C mutation, patients with KRAS codon 13 mutations have had few targeted treatment options. Although KRAS codon 13 mutations account for a relatively small proportion of lung cancers (around 5% to 7% of KRAS-mutant NSCLC), researchers estimate that survival outcomes of up to 11,400 patients globally per year could be improved if they had access to targeted therapies developed specifically for these tumours.
This new research led by Dr Colin Lindsay from The Christie NHS Foundation Trust and Angeliki Malliri at The University of Manchester shows that KRAS codon 13 mutations, while being weaker KRAS mutations, interact with other aggressive genetic alterations, including mutations in BRAF, NF1, STK11 and KEAP1, to help tumours grow and spread.
The research team, including Dr Will McDaid and Dr Helen Adderley, at the Manchester Cancer Research Centre worked in collaboration with US biotech company Revolution Medicines to investigate a new experimental drug called RMC-8839, which is a KRAS G13C-selective inhibitor designed to specifically target tumours carrying the KRAS G13C mutation by turning off the signals that tell the cancer cells to grow. In the laboratory, RMC-8839 successfully blocked KRAS G13C activation and reduced tumour cell growth.
The most striking finding was that KRAS G13C tumours appeared unusually sensitive to chemotherapy compared with other KRAS-driven cancers. When researchers combined RMC-8839 with chemotherapy, the results were significant, dramatically shrinking and eradicating tumours in cancer models, suggesting a potentially effective treatment combination for this genetic subtype.
Dr Colin Lindsay, consultant oncologist from The Christie NHS Foundation Trust said. “Once we understand these changes and develop the first drug to target them, moving from the lab into the clinic usually happens quite quickly. 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.”
Professor Angeliki Malliri, Professor of Cell Biology at The University of Manchester said: “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 needed to determine whether the combination of RMC-8839 and chemotherapy can improve survival in patients with KRAS G13C-mutant lung cancer.
This study is supported by Cancer Research UK, The Christie Charity and the Manchester Cancer Research Centre. It was funded by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (BRC) and by Revolution Medicines. Data was provided by Genomics England.
