By Gilang Cahya 
Researchers at the Francis Crick Institute, in collaboration with Revolution Medicines, have achieved a significant breakthrough in the fight against lung cancer, demonstrating that a novel combination of targeted therapies can effectively overcome resistance to immunotherapies in mouse models. This groundbreaking research, published today in the prestigious journal Nature Communications, suggests that a multi-pronged approach to targeting tumours simultaneously may unlock the potential of immunotherapies for a wider range of patients, including those with historically non-responsive cancers.
The Challenge of Immunotherapy Resistance in Lung Cancer
Lung cancer remains a leading cause of cancer-related deaths worldwide, and while immunotherapies have revolutionized treatment paradigms in recent years, a substantial proportion of patients do not respond to these life-saving drugs. Immunotherapies, such as immune checkpoint inhibitors, work by unleashing the patient’s own immune system to recognize and attack cancer cells. However, tumours can develop sophisticated mechanisms to evade immune detection, often described as "immune cold" tumours, which are characterized by a lack of immune cells within the tumour microenvironment. This inherent resistance poses a significant hurdle in achieving durable responses for many lung cancer patients.
Historically, the development of targeted therapies for lung cancer has focused on specific genetic mutations that drive tumour growth. For instance, the KRAS gene is frequently mutated in non-small cell lung cancer (NSCLC), the most common form of lung cancer. While KRAS inhibitors have shown promise, resistance mechanisms often emerge, limiting their long-term efficacy. Similarly, the SHP2 protein, a phosphatase that plays a crucial role in cell signalling pathways, has been identified as a potential target in cancer therapy, as its dysregulation can promote tumour growth and suppress anti-tumour immunity.
A Strategic Combination: Targeting Multiple Pathways
The research team at the Francis Crick Institute, led by Julian Downward and Miriam Molina-Arcas, embarked on a mission to address this challenge by exploring a combinatorial therapeutic strategy. Their approach involved simultaneously targeting multiple key pathways that contribute to tumour growth and immune evasion. The core of their strategy revolved around a triplet combination designed to:
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Inhibit KRAS G12C: This component targets a specific, common mutation in the KRAS gene found in many lung cancers. By blocking this mutated KRAS protein, the researchers aimed to halt a critical growth signal within the cancer cells. This represented a newly identified KRAS G12C inhibitor, indicating the forefront of drug development in this area.
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Block SHP2: The second compound in the triplet was designed to inhibit the SHP2 protein. As mentioned, SHP2 plays a multifaceted role in cancer, often promoting tumour cell survival and proliferation. Furthermore, SHP2 can also negatively impact the immune system’s ability to fight cancer. By blocking SHP2, the researchers aimed to disrupt these pro-tumourigenic and immunosuppressive functions.
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Activate Immune Checkpoint Inhibitors: The third and arguably most crucial component of the combination was an immune checkpoint inhibitor. These drugs are designed to block proteins, such as PD-1 or CTLA-4, that cancer cells exploit to shield themselves from immune surveillance. By releasing these "brakes" on the immune system, checkpoint inhibitors allow T cells, a type of immune cell, to recognize and attack cancer cells more effectively.
The critical insight of this research lies in the hypothesis that by combining these three agents, they could create a synergistic effect. The targeted inhibition of KRAS and SHP2 was hypothesized to not only reduce tumour burden directly but also to prime the tumour microenvironment, making it more susceptible to the action of immune checkpoint inhibitors. In essence, the targeted compounds were thought to provide a "window of opportunity" for the immune system to engage and eliminate the cancer.
Remarkable Results in Pre-Clinical Models
The research team meticulously tested this triplet combination in mouse models of lung cancer. The results were highly encouraging. In mice possessing functional immune systems, the combination therapy led to significant tumour shrinkage. In a notable subset of these mice, the tumours were completely eradicated, offering a glimpse of potential curative outcomes.
Beyond immediate tumour regression, the study also highlighted the long-term benefits of this approach. The mice that experienced tumour eradication also demonstrated increased resistance to the recurrence of lung cancer after treatment. This suggests that the therapy not only cleared existing tumours but also potentially induced a form of immunological memory, equipping the body to fight off any lingering cancer cells or newly developing ones.
Perhaps the most significant finding of the study was its impact on "immune cold" tumours. These are notoriously difficult to treat with conventional immunotherapies because they lack the necessary immune cell infiltration required for the therapy to be effective. However, in these resistant models, the triplet combination demonstrated an unprecedented ability to sensitize the tumours to immune checkpoint inhibitors. This implies that the targeted agents could effectively "warm up" these cold tumours, making them visible and vulnerable to immune attack.
Unveiling the Mechanism: A Window of Opportunity
The researchers posit that the combined action of the KRAS and SHP2 inhibitors creates a more favourable environment for the immune system. By inhibiting these key signalling pathways, the targeted drugs may reduce the expression of immunosuppressive factors within the tumour and increase the infiltration of immune cells. This, in turn, allows the immune checkpoint inhibitors to more effectively activate and direct these immune cells to eliminate the cancer.
Julian Downward, Principal Group Leader of the Oncogene Biology Laboratory at the Crick and co-senior author, elaborated on the significance of these findings. "Blocking genes like KRAS in lung cancer has led to some exciting new developments, but we still see problems with resistance," he stated. "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." This statement underscores the dual benefit of the therapy: direct tumour attack and immune system activation, even in previously unresponsive tumours.
The Road Ahead: Human Trials and Future Implications
The success observed in mouse models is a crucial step, but the ultimate goal is to translate these findings into effective treatments for human patients. The researchers acknowledge this next vital phase. Given the promising pre-clinical results, an evaluation of this combination in human clinical trials for lung cancer patients is a logical and highly anticipated next step. Such trials will be essential to determine if the triplet therapy elicits similar responses and safety profiles in humans.
However, the path to clinical implementation is not without its challenges. Combining multiple therapeutic agents often raises concerns about potential side effects. Research will be needed to thoroughly understand and effectively manage any adverse events associated with this specific combination. This will involve careful dose optimization, monitoring of patient responses, and the development of strategies to mitigate toxicity.
Panos Anastasiou, a PhD student in the Oncogene Biology Laboratory at the Crick and the first author of the study, emphasized the broader implications of their work. "Our work stresses the importance of targeting tumours from all angles, especially ones that don’t respond easily to treatment," he commented. "It will be critical to see if the combination of inhibitors works in the same way in humans." His statement highlights the fundamental shift in thinking that this research represents – moving towards a more holistic and integrated approach to cancer therapy.
A Collaborative Effort and Funding Landscape
This significant research effort was a testament to extensive collaboration. Panos Anastasiou worked closely with various specialized teams at the Crick, including the Experimental Histopathology, Bioinformatics and Biostatistics, Genomics, Scientific Computing, Flow Cytometry, Cell Services, and Biological Resources teams. This interdisciplinary approach was crucial for the comprehensive execution and analysis of the study.
The research was underpinned by a collaborative research agreement with Revolution Medicines, a company at the forefront of developing targeted therapies for cancer. This partnership provided critical resources and expertise. Additional funding was secured from the European Union and the Wellcome Trust, underscoring the broad support and recognition for this innovative research direction.
Broader Impact on Cancer Treatment Strategies
The implications of this study extend beyond lung cancer. The principle of combining targeted therapies with immunotherapies to overcome resistance could be applicable to a wide range of other cancer types that currently exhibit poor responses to immunotherapy. As our understanding of tumour biology and immune evasion mechanisms deepens, combinatorial approaches like the one demonstrated here are likely to become increasingly central to future cancer treatment strategies.
The research also highlights the importance of addressing tumour heterogeneity and the complex interplay between cancer cells and the immune system. By targeting multiple vulnerabilities simultaneously, researchers are developing more robust and resilient therapeutic interventions. The success of this triplet therapy in sensitizing "immune cold" tumours is particularly noteworthy, as it opens up new avenues for treating a significant unmet need in oncology.
In conclusion, the findings from the Francis Crick Institute and Revolution Medicines represent a pivotal advancement in the quest to conquer lung cancer and potentially other difficult-to-treat malignancies. By demonstrating the power of a multi-pronged attack on cancer, this research offers renewed hope for patients who have previously found themselves with limited treatment options. The coming years, with the progression of this research into human trials, will be keenly watched by the scientific and medical communities alike.
