In the world of cancer, lung cancer is considered to be the most notorious one in terms of both incidence and mortality in the general population. This is due to a rise in a number of people who smoke, have a sedentary lifestyle, and increased exposure to radiation. Multiple drugs have been approved for the treatment of lung cancer, however, most cancers have developed resistance against them. In a significant breakthrough for lung cancer treatment, researchers from the Francis Crick Institute have discovered that combination therapy can greatly improve the response to immunotherapy.
By using this innovative approach, which combines different therapeutic methods, the study highlights how combination therapy can overcome resistance to immunotherapy, offering new hope for patients with lung cancer.
Discovery
Researchers at the Francis Crick Institute, in collaboration with Revolution Medicines, have tested a combination of treatments in mice with lung cancer and shown that these allow immunotherapies to target non-responsive tumours.
Their findings show that targeting tumours in different ways simultaneously might increase response to treatments.
In research published in Nature Communications, the scientists tested a combination of tool compounds in mice with lung cancer. These compounds were used to represent:
- Targeted drugs that block a cancer-causing protein called KRAS G12C. These have been approved for use in lung cancer, but often fail to benefit patients in the long term because the tumours develop resistance to these medicines over time.
- Immunotherapy drugs. These are designed to stimulate the immune system to fight the tumour, but only 20% of people with lung cancer respond, as tumours often block immune cells from entering.
The researchers combined a newly identified KRAS G12C inhibitor, with a compound that blocks a protein called SHP2, which inhibits cancer cells and can also activate tumor immunity.
These two inhibitors were combined with an immune checkpoint inhibitor, which blocks proteins that help the cancer cells hide from the immune system.
In mice with functional immune systems, the triplet combination therapy shrank the tumours and, in some mice, fully eradicated them. These mice were also more resistant to the lung cancer coming back after treatment.
The team believes that these targeted compounds provide a window of opportunity where the immune checkpoint inhibitor can kick into gear and allow the body’s natural defences to attack the tumour.
Even in mice with ‘immune cold’ tumours that are normally unresponsive to immunotherapy, the combination allowed tumours to become sensitised to the immune checkpoint inhibitors.
Given the success in studies with mice, an evaluation of the combination could be conducted in people with lung cancer to determine if it has a similar effect. Research will also be needed to understand and counteract potential side effects associated with combining treatments.
Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick, and co-senior author with Miriam Molina-Arcas, said: “Blocking genes like KRAS in lung cancer has led to some exciting new developments, but we still see problems with resistance. We’ve now been able to report partial or complete eradication of tumours in mice by combining KRAS and SHP2 inhibitors with immunotherapy. We also showed that this combination therapy allows ‘immune cold’ tumours to respond to the body’s own defences.”
Panos Anastasiou, PhD student in the Oncogene Biology Laboratory at the Crick, and first author, said: “Our work stresses the importance of targeting tumours from all angles, especially ones that don’t respond easily to treatment. It will be critical to see if the combination of inhibitors works in the same way in humans.”
Panos worked with the Experimental Histopathology, Bioinformatics and Biostatistics, Genomics, Scientific Computing, Flow Cytometry, Cell Services, and Biological Resources teams at the Crick. The research was funded by a collaborative research agreement with Revolution Medicines, with additional funding from the European Union and the Wellcome Trust.
KRAS
KRAS is a protooncogene that is required for cell growth and differentiation. Mutations occurring in this protooncogene can lead to neoplastic cellular growth. It belongs to the family of Ras gene signal transducers that relay signals from receptor activation to the nucleus.
Ras is bound to the GDP during an inactive state. During receptor binding, GDP is replaced with GTP which activates Ras. This activated Ras travels down from the cell membrane to the nucleus carrying growth and differentiation signals. Afterwards, GTP is replaced with GDP again rendering the inactivation of Ras with the help of the enzyme GTPase. Mutation occurs in Ras causing reduced response to GTPase, which leads to prolonged activated Ras function.
Out of all the mutations, glycine to cysteine substitutions at codon 12 (G12C) is one of the most common mutations causing lung cancer (most commonly adenocarcinoma).
KRAS mutations can also cause colorectal (via the adenoma-carcinoma pathway) and pancreatic cancers.
SHP-2 protein
The PTPN11 gene encodes the protein tyrosine phosphatase SHP2, which plays a crucial role in controlling the Ras/MAPK signaling pathway. This pathway is activated by several growth factor receptors, such as EGFR and MET.
SHP2 stimulates RAS activity by removing inhibitory phosphotyrosines, ultimately leading to the activation of Ras and its downstream effectors. As a result, SHP2 is a vital regulator of Ras-mediated signaling, especially in cancers triggered by receptor tyrosine kinase (RTK) activation.
Various cancers, including lung cancer, have been linked to SHP2 mutations or abnormal activation. Additionally, SHP2 is involved in promoting bypass signaling through the Ras/MAPK pathway, which can lead to resistance to targeted therapies like EGFR inhibitors.
PD-1
PD-1 and CTLA-4 are immune checkpoint inhibitors that decrease immune T-cell activation and function. PD-1 are surface receptors present on T-cells. It binds to PD-L1/2 present in tumor cells and causes PD-1 activation leading to repression of T-cell function. This mechanism can be inhibited by developing drugs against
- PD-1 – pembrolizumab, cemiplimab
- PD-L1/2 – atezolimumab, avelumab
It was first discovered in 1992 by Tasuku Honjo who was awarded the Nobel Prize in Physiology or Medicine in 2018. He was awarded along with James. P. Allison for his discovery of another immune checkpoint inhibitor – CTLA-4.
Future implications of combination therapy
KRAS mutation is one the most prevalent cause of lung cancers worldwide especially NSCLC (non-small cell lung cancer). As precision medicine continues to advance, combination therapies have emerged as a promising strategy to improve treatment efficacy, delay resistance, and enhance patient outcomes. Here are potential future implications for combination therapies especially in the field of lung cancer.
- Overcoming drug resistance: Combination therapies can block multiple cancer pathways, making it harder for tumors to develop resistance.
- Enhanced efficacy: Targeting multiple signaling pathways simultaneously increases the overall effectiveness of treatment.
- Synergy with immunotherapy: Combining immunotherapy with targeted therapies boosts the immune system’s ability to fight lung cancer.
- Reduced toxicity: Optimized dosing of combination therapies may lower side effects while maintaining efficacy.
- Personalized medicine: Biomarker-driven therapies allow for tailored combination treatments based on the patient’s specific genetic mutations.
- Long-term remission potential: Combination approaches could help achieve more durable, long-lasting responses.
- New drug development: Future treatments will likely focus on drugs designed to work synergistically with existing therapies.
- Clinical trial expansion: More trials will be needed to explore the safety and effectiveness of combination therapies.
Source: The Francis Crick Institute
Journal Reference:
Anastasiou, P., Moore, C., Rana, S. et al. Combining RAS(ON) G12C-selective inhibitor with SHP2 inhibition sensitises lung tumours to immune checkpoint blockade. Nat Commun, 2024 DOI: 10.1038/s41467-024-52324-3
