Lay summary review on mechanisms of a new clinical drug combination

Lay Summary

Title: A proposal on investigating the mechanisms of a new clinical drug combination

Why is this research needed?

Breast cancer, particularly aggressive forms like triple-negative breast cancer (TNBC), remains one of the most challenging cancers. Despite advancements in treatment, chemotherapy remains a primary option for many TNBC patients. However, chemotherapy often causes side effects and is not always effective. A breakthrough treatment called sacituzumab govitecan (SG) has shown significant promise. This treatment combines an antibody that targets cancer cells with a chemotherapy drug, delivering the latter directly to the tumour while sparing healthy tissue. It has significantly improved survival rates for patients with metastatic breast cancer (12.1 months compared to 6.7 months for standard chemotherapy), and was approved in the UK in 2022.

However, some patients do not respond to SG, and others eventually develop resistance to the treatment, reducing its long-term benefit. To address this challenge, our research will study how SG can be combined with a WEE1 inhibitor, a drug that targets a key protein involved in the DNA damage response. We believe this combination could help overcome resistance, making cancer cells more sensitive to SG and improving treatment outcomes. Indeed, in 2025, our initial findings have led to the first major clinical trial investigating the combination of SG and WEE1 inhibitor.

What will this research achieve?

Our research has three goals. First, we want to study how SG and WEE1 inhibitor work together to make cancer cells more responsive to treatment. By studying this interaction, we hope to uncover why the combination is more effective than using either drug alone. Second, we want to identify the mechanisms that enable some cancer cells to resist this novel combination therapy. This knowledge will help us proactively develop strategies to prevent future resistance. Third, we want to optimise the treatment regimen by exploring different ways to combine and administer the drugs, with the ultimate goal to maximise efficacy while minimising side effects.

How will we conduct this research?

To achieve the above goals, we will conduct experiments using TNBC cells, to test how they respond to the combination. Additionally, we will use start-of-the-art genetic sequencing methods to examine changes in the cancer cells before and after treatment, helping us understand the mechanisms underlying drug sensitivity versus resistance. We will validate our findings using patient specimens collected from the clinical trial, which will provide real-world data and ensure our research is aligned with actual clinical scenarios.

What impact will this research have?

This research has the potential to improve outcomes for breast cancer patients. By understanding how the drug combination works, we may be able to identify predictive biomarkers of sensitivity, which can lead to more personalised treatment. For example, these biomarkers will enable doctors to identify patients who will have the greatest success of responding to the combination.

Equally, studying the mechanisms of resistance to this combination will help us predict which patients are at risk of developing resistance. Identifying these high-risk patients will allow us to develop strategies to overcome resistance before it emerges, ensuring that patients can benefit from the therapy for a longer period.

Finally, by optimising the dosing regimens, we aim to develop treatment strategies that maximise efficacy, minimise side effects and improve the overall patient experience, making the treatment more manageable and less disruptive.

Together, this research may improve both survival rates and quality of life for breast cancer patients by providing kinder and smarter treatment options.

Future research

This research will lay the groundwork for new preclinical studies on the mechanisms of drug response. Specifically, by identifying how cancer cells respond to the combination, we can refine existing therapies and explore new therapeutic possibilities.

Equally, this research could lead to clinical trials testing the drug combination in various settings, including specific breast cancer patient subgroups, and optimised treatment regimens. Such trials would provide valuable insights into how these therapies can be best utilised to maximise patient outcomes.

In sum, this research has the potential to advance personalised treatments, ensuring that patients have the best chance of surviving breast cancer and maintaining a good quality of life.