What is it about?

Most proteins in our cells contain small regions that are sticky and can cause proteins to clump together or 'aggregate'. These sticky regions or aggregation-prone regions (APRs) as we call them, are usually confined in the core of the folded protein to prevent undesirable protein aggregation that would disable the protein. There are however many proteins that researchers deliberately want to disable to treat diseases. A good example is the oncoprotein KRAS that plays an important role in cancer development. In this study it was discovered that KRAS can be disabled using a therapeutic molecule that contains a sticky region of KRAS. These sticky fragments are taken up by the cancer cells, bind to the KRAS protein and induce its aggregation, which causes the cancer cells to die.

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Why is it important?

Much research effort is spent on finding therapeutic molecules to disable disease-driving proteins. This is a major challenge because many proteins are difficult to drug with current classes of therapeutics. Our work showed that the presence of the APRs is an intrinsic vulnerability that can be therapeutically exploited. Since the APR regions play a role in protein folding they are present in almost all proteins. This means that there are in principle many other disease-driving proteins that can be targeted using aggregate fragments.

Perspectives

Development of novel therapeutic technologies requires solid basic science, innovative thinking, teamwork and perseverance. This publication definitely contains all four ingredients. Step by step we will get closer to finding effective therapies for all cancers.

Kobe Janssen
Associatie KU Leuven

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This page is a summary of: Exploiting the intrinsic misfolding propensity of the KRAS oncoprotein, Proceedings of the National Academy of Sciences, February 2023, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2214921120.
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