New way to target cancer diversity and evolution

Scientists have revealed in detail a vital molecule involved in the combination of genetic information within cells, thus opening the targeting potential of this family's proteins to fight cancer diversity and evolution.

A team from the Cancer Institute in London has discovered the three-dimensional structure and function of this "mix n match" protein, which controls a process related to cancer progression and drug resistance.

Researchers believe the study paves the way for a potentially exciting new way of tackling drug-resistant cancers and will explore this possibility in the new 75 million-dollar Cancer Drug Discovery Center. from £.

The study is published in Biochemical Journal Today (14 September), it was funded by Cancer Research UK and by the Faringdon Fund, created by the Cancer Institute (ICR) to launch high-risk projects after a generous philanthropic donation.

ICR researchers have studied the structure and function of a molecule called DHX8. This belongs to a class of proteins involved in a fundamental life process called "alternative splicing," which affects 95% of human genes.

The splicing takes place once the DNA code has been copied into the RNA, with some pieces cut out and the rest glued to create a final code that is translated into protein.

In alternative splicing, the RNA bits that are cut or preserved can be modified to create multiple proteins from a single gene, thereby increasing the diversity of proteins available to the cells.

When alternative splicing goes wrong, it can lead to protein changes in the cells, which can lead to cancer or fuel the diversity, evolution, and resistance to cancer drugs.

The splicing is performed by a complex composed of proteins and RNA, which constantly changes during the cutting and gluing of RNA. DHX8 is a crucial member of this complex and contributes to the release of the finished RNA in the cell so that it can be translated into protein.

In this new study, researchers examined how the human DHX8 protein binds to RNA and acts to unravel RNA from the rest of the splicing mechanisms.

They also determined the first high-resolution X-ray crystalline structures of DHX8 with and without RNA, allowing them not only to visualize the molecular structure of the protein, but also to obtain key clues on its function.

In particular, the study highlighted the roles of specific structural regions of DHX8, including the so-called "DEAH pattern", "hook loop" and "hook loop" regions, all of which have been shown to be vital for the operation of DHX8.

The researchers then want to study in more detail how DHX8 can contribute to cancer – and believe that their study will open pathways to block protein family members as a promising new approach to treatment.

Trying to combat cancer diversity is one of the central strategies ICR pursues as part of an innovative research program to overcome the ability of cancers to adapt, evolve and become drug-resistant. .

ICR, a charity and research institute, raises £ 14 million from a £ 75 million investment in the new Cancer Research Center to offer an innovative program of anti-cancer therapies -evolution".

Dr. Rob van Montfort, Head of Study, Team Leader for Success Discovery and Structural Design at the Institute of Cancer Research in London, said:

"Our study shed new light on the structure and function of a crucial protein involved in the process of alternative splicing, in which genetic information is mixed and associated to create multiple protein molecules at different times. from a single gene.

"Cancer cells leverage alternative splicing to diversify, evolve, and escape the regulatory mechanisms of the body." By determining the detailed molecular structure of one of the key protein molecules involved in Alternative splicing, we have opened new potentially interesting pathways for the treatment of cancer. "

Professor Paul Workman, co-author of the study, general manager of the London Cancer Institute, said:

"We are excited to further explore these" mix and match "proteins, as we believe that our discoveries open a new pathway to help block cancer pathways and potentially overcome drug resistance.

"This is exactly the kind of approach we plan to take in our new pioneering Cancer Drug Discovery Center, which, once completed, will house the first" Darwinian "drug discovery program in Canada. world, to address the dual challenge of cancer evolution and drug resistance.

Emily Farthing, Head of Research Information at Cancer Research UK, said:

"This research provides valuable insights into how cancer cells hijack a process from our cells to make them more diverse and allow them to escape treatment, although more work is needed to tap into the process. these results, this research could pave the way for new anticancer therapies. " In the future. "