Cancer drug resistance causes and categories identified

All cancer mutations that cause drug resistance fall into one of four categories. New research has detailed each type, helping to uncover targets for drug development and identify potential second-line therapies. 

In a new large-scale study, researchers used CRISPR gene editing and single-cell genomic techniques to map the genetic landscape of drug resistance in cancers, including colon, bone and lung. This work was a collaboration between researchers at the Wellcome Sanger Institute, EMBL’s European Bioinformatics Institute (EMBL-EBI) and Open Targets.

The research, published in Nature Genetics, investigates the effect of mutations on the sensitivity to ten cancer drugs. It also identifies possible effective second-line treatments based on a person’s genetic makeup. 

“Cancer cells developing resistance to treatments is a huge problem, and having a rapid way to identify these mutations in patients and understand how to combat them is key to treating cancer,”  said Matthew Coelho, Research Fellow at Wellcome Sanger Institute and Open Targets. “Our study details how mutations fall into four different groups, which might need different treatment plans. For example, if there are drug addiction mutations, taking a break from treatment may help.”

Identifying drug resistance mutations  

One of the major challenges in cancer treatment is drug resistance. Cancer cells mutate and over time they become less responsive to therapies. Once cancer becomes resistant to the initial treatment, the following therapies – known as second-line therapies – can be limited. Understanding what molecular changes are causing the resistance can help inform clinical paths for specific mutations. 

However, current methods for identifying drug-resistance mutations require multiple samples from patients collected over a long time, making this a time-consuming, costly and invasive process. For this study, researchers used CRISPR gene editing and single-cell genomic techniques to investigate the impact of multiple drugs across human cancer cell lines and organoid cell models. 

“The functional framework that we have built allows researchers to start to piece together a complete map of common DNA changes seen during cancer treatment, adding to our collective knowledge,” said Magdalena Strauss Lecturer at University of Exeter, former Research Fellow at EMBL-EBI. “It also highlights mutations that could be used as biomarkers, highlighting cancer cells that are more sensitive to certain treatments, which could help inform future clinical trials.”

Four categories of cancer mutations 

The team found that cancer mutations fall into four different categories depending on the impact of the DNA change. 

1. Drug resistance mutations – genetic changes in the cancer cell that lead to the drug being less effective. 
2. Drug addiction mutations – these lead to some of the cancer cells using the drug to help them grow, instead of destroying them. 
3. Driver mutations – gain-of-function genetic changes that allow cancer cells to use a different signalling pathway to grow, avoiding the pathway that the drug may have blocked. 
4. Drug-sensitising variants – genetic mutations that make the cancer more sensitive to certain treatments and could mean that patients with these genetic variations in their tumour would benefit from particular drugs. 

“This research brings us one step closer to being able to match combination or second-line therapies to a person’s genetic make-up, to try and ensure that treatments are as effective and personalised as possible,” said Mathew Garnett, Group Leader at the Wellcome Sanger Institute and member of the scientific leadership team for Open Targets. “Additionally, we believe that our new systematic approach will be important for understanding genetic mechanisms of resistance to new drugs in the future. This could help even before the emergence of resistance in the clinic, and these early insights will improve developing cancer treatments.”

This press release was originally published on the Wellcome Sanger Institute website.