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Targeting a specific protein halts tumour growth

8 February 2021
Appeared in BioNews 1082

Disrupting a specific protein interaction causes tumours to shrink, researchers in the US have found. 

A new study has discovered a critical interaction with the protein MYC, which could open new avenues for cancer treatment. Previous efforts to target MYC, which is associated with numerous cancers, have been limited by its 'undruggable' structure.

'MYC becomes the nitro in the tank, driving relentless rounds of cell duplication and division,' said senior author Professor William Tansey, of Vanderbilt University in Nashville, Tennessee. He added: 'If we can validate the physical contact between MYC and a protein, we can go after it therapeutically.'

The study, published in the journal eLife, investigated the interaction between MYC and the protein Host Cell Factor-1 (HCF-1) in a mouse model of Burkitt Lymphoma. MYC binds DNA while at the same time binding protein partners, including HCF-1, to exert changes in gene expression. The authors posed that cancer-promoting functions of MYC could be disrupted by targeting the interface of the protein interaction.

The team engineered an inducible mutation into MYC in cancer cells so it could no longer interact with HCF-1, and injected the cells into mice. After allowing tumours to grow, the research team switched on the mutation, and the tumours began to shrink. In tumours where the MYC/HCF-1 interface was mutated, all mice survived the duration of the study. The tumours of mice injected with non-mutated MYC/HCF-1 continued to grow.

MYC proteins are estimated to be linked to over a third of all cancers, and regulate thousands of genes. Professor Tansey previously referred to drug-targeting of MYC as the 'Holy Grail of the targeted cancer therapy world,' but efforts to inhibit it directly have been limited by its lack of structure.

In 2015, Professor Tansey's team discovered another protein that interacted with MYC and drove cancer growth, called WDR5. Similar to its interaction with HCF-1, a small and conserved portion of MYC docked with the protein, which could be amenable to targeting with drug inhibitors. Elsewhere, in 2019 a research team led by Dr Constantinos Koumenisat at the University of Pennsylvania examined the MYC-binding partner ATF4. Published in Nature Cell Biology, they found that blocking ATF4 binding caused cancer cells to die in mouse models of colon cancer and lymphoma.

Professor Tansey's team are hopeful that by identifying binding partners such as HCF-1 and the small conserved regions of MYC where they bind, drugs can be developed to indirectly disrupt MYC.

'What's interesting is that we don’t need to take away all of the MYC function,' explained Professor Tansey. 'Like an Achilles heel, we only need to go after a very specific interaction.'

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