Professor Paul Huang
Cancer Research Institute
Awarded: £119,960
Research led by Professor Paul Huang, Dr Mark Elms, and Dr Andrew Jenks, as part of a Sarcoma UK–funded PhD, discovered a promising way of tackling resistance to a group of cancer drugs used for soft tissue sarcoma known as multi-target tyrosine kinase inhibitors (mTKIs).
Key findings
- The researchers studied a group of drugs called multi-target tyrosine kinase inhibitors (mTKIs) to understand how they work in soft tissue sarcoma cells and why drug resistance develops.
- The team found that the four mTKIs tested acted through similar molecular mechanisms, and resistance arose in similar ways.
- This suggests that switching from one mTKI to another is unlikely to be effective once resistance occurs.
- When cells become resistant to an mTKI, they can develop new weaknesses. These new vulnerabilities are known as collateral sensitivities.
- One example of collateral sensitivity was found in soft tissue sarcoma cells that became resistant to an mTKI called sitravantinib
- As these cells became resistant to sitravantinib they became sensitive to another drug called infigratinib. This points to a potential strategy to overcome drug resistance.
What are mTKIs?
Multi-target tyrosine kinase inhibitors (mTKIs) are a type of targeted cancer therapy that block signals from proteins called tyrosine kinases, which cancer cells use to grow and divide uncontrollably.
By shutting down these signals, these drugs slow or stop tumour growth.
However, many patients with soft tissue sarcoma eventually stop responding to these treatments, or do not respond at all, because cancer cells can find ways to develop drug resistance to these therapies.
What the researchers did
The team studied four different mTKIs in soft tissue sarcoma cells. They found that they all worked in similar ways, and resistance developed through similar mechanisms.
Therefore, switching from one mTKI to another after drug resistance develops is unlikely to help.
The team found that when cells became resistant to an mTKI they developed new weaknesses, known as collateral sensitivities.
For example, soft tissue sarcoma cells resistant to the mTKI sitravatinib became sensitive to another drug called infigratinib.
What this means for patients
Rather than switching between similar drugs, which can lead to resistance, the team have identified collateral sensitivity ‘weak spots’.
This is an exciting finding as this could be exploited to help patients whose cancers have become resistant. This could lead to better patient outcomes with multiple lines of therapy available.
Clinical trials would need to be done to see whether these effects are seen for people living with soft tissue sarcoma.
Next steps
This study demonstrated that exploiting collateral sensitivity can be an effective strategy for overcoming resistance to mTKIs in soft tissue sarcoma.
These findings could inform the design of future clinical trials which could test whether exploiting these new drug vulnerabilities can help patients whose cancers have become resistant to current treatment options.
People living with soft tissue sarcoma invariably develop or have resistance to currently approved mTKIs and treatment following the development of resistance is lacking. This research is exciting as it reveals potential new pathways to overcome drug resistance and could allow for more durable long-term treatment paradigms for patients – Dr Mark Elms
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