Researchers from Karolinska Institutet have developed a new way to understand how cancer drugs interact with different forms of protein. The study has been published in Nature Communications.
Traditionally, proteins have been considered identical if they come from the same gene. However, the new method makes it possible to distinguish subtle protein variants, known as functional proteoforms. These variants can affect how they interact with drugs, which in turn can influence both the effectiveness of the treatment and its side effects.
"In this study, we have extended our previous methodology to better understand the target landscape of ibrutinib, a widely used drug in treatment of certain leukemias. Apart from identifying previously unknown targets of ibrutinib we could for the first time clearly show that ibrutinib interacts differently with different variants of the same protein," says Rozbeh Jafari , associate professor at the Department of Oncology-Pathology , Karolinska Institutet who led the study.
The new method is based on thermal proteomics, where researchers measure specific physical differences between protein forms, known as their thermostability. By measuring the thermostability of individual protein fragments, called peptides, the researchers have previously been able to distinguish peptides with similar patterns. This makes it possible to discover functional proteoforms.
In a further development of the technology, researchers have studied how drugs affect proteoforms and their thermostability. In studies of ibrutinib, researchers observed that the drug affected the thermostability of specific functional proteoforms. By studying how drugs affect the thermostability of proteins, researchers have been able to identify specific functional proteoforms and their interactions with drugs.
Implications for drug development
"Being able to identify these small details could ultimately have a big impact on interpretation of disease biology and drug response. Functional proteoforms and their interactions with cancer therapies have important implications for drug development and precision medicine, and studying them could pave the way for more effective treatments," says Isabelle Leo , PhD student at the same department at Karolinska Institutet and the study's first author.
Looking ahead, the researchers plan to further develop the method to contribute to a better understanding of how drugs interact with complex protein networks within our cells. This represents a critical stepping stone to more personalized and effective treatments.
The research was financed by The Swedish Cancer Society, Swedish Childhood Cancer Fund, The Swedish Research Council, Cancer Society in Stockholm and King Gustaf V Jubilee Fund.
Publication
" Functional proteoform group deconvolution reveals a broader spectrum of ibrutinib off-targets ", Isabelle Rose Leo, Elena Kunold, Anastasia Audrey, Marianna Tampere, Jürgen Eirich, Janne Lehtiö, Rozbeh Jafari. Nature Communications, online 25 February 2025, doi: 10.1038/s41467-024-54654-8.
