Promising medication combination to treat an 'undruggable' type of lung cancer
· Medical Xpressedited by Lisa Lock, reviewed by Andrew Zinin
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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. The 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 that 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 for up to 11,400 patients globally each year could be improved if they had access to targeted therapies developed specifically for these tumors.
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 tumors grow and spread.
The research team, including Dr. Will McDaid and Dr. Helen Adderley at the Manchester Cancer Research Center, worked in collaboration with U.S. biotech company Revolution Medicines to investigate a new experimental drug called RMC-8839, which is a KRAS G13C-selective inhibitor designed to specifically target tumors 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 tumor cell growth.
The most striking finding was that KRAS G13C tumors 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 tumors 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 multidisciplinary 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 toward 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.
Publication details
William J. McDaid et al, Targeting KRAS codon 13 mutations using direct combination approaches in non-small cell lung cancer, Cancer Discovery (2026). DOI: 10.1158/2159-8290.cd-25-0884
Journal information: Cancer Discovery
Key medical concepts
Carcinoma, Non-Small-Cell Lung
Clinical categories
OncologyClinical pharmacology Provided by University of Manchester Who's behind this story?
Lisa Lock
BA art history, MA material culture. Former museum editor, paramedic, and transplant coordinator. Editing for Science X since 2021. Full profile →
Andrew Zinin
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