Discovery of AMBRA1 enzyme may help cancer treatment

Researchers have discovered a novel enzyme called AMBRA1 that has eluded scientists for over 25 years; its discovery may revolutionise cancer treatment.

The study, led by researchers at NYU Grossman School of Medicine, analyses the propensity for human cell division, with most of these divisional stages promoted by proteins called cyclins. Their inquisition found that the AMBRA1 enzyme targets an essential class of cyclins for destruction by cellular machines that break down proteins.

The findings demonstrate that the AMBRA1 enzyme crucially controls cyclins throughout embryonic development, with occasions where they malfunction, subsequently leading to lethal cell overgrowth that causes cancer. The team are optimistic that their discovery means that an existing drug class will enable them to reverse these defects in the future.

Michele Pagana, the author of the study, said: “Our study clarifies basic features of human cells, provides insights into cancer biology and opens new research avenues into potential treatments.”

To conduct their study, the scientists analysed the three D-type cyclins that link with enzymes called cyclin-dependent kinases (CDKs), explicitly CDK4 and CDK6, that cause cell division. Sensationally, they found that AMBRA1 attaches molecular tags to all D-type cyclins, labelling them for destruction.

To understand the role of AMBRA1 in cancer, the authors utilised a litany of patient databases, from this inferring that people displaying a lower-than-normal expression of AMBRA1 had a less likely chance of surviving diffuse large B-cell lymphoma.

The researchers next order of business was to understand the influence of AMBRA1 as a tumour suppressor – investigating cancer cell growth in mouse models of diffuse large B-cell lymphoma, finding that cells deficient in AMBRA1 mutated up to three-time as much as those with the gene. Further studies led by Stanford University and the Danish Cancer Society Research Centre have divulged that absent or disabled AMBRA1 is a crucial factor in lung cancer.

Finally, AMBRA1 may help to innovate and redesign cancer therapies currently in use, as drugs that inhibit CDK4 and CDK6 garner a weaker response from some patients. The team found that lymphomas that lack AMBRA1 are less receptive to CDK4 and CDK6 inhibitors. The reasoning for this is that when the AMBRA1 gene is not present, levels of D-type cyclins reach a point where they form complexes with another CDK, which due to its composition, cannot be activated by CDK4/6 inhibitors.

Daniele Simoneschi, the co-author of the study, said: “This makes AMBRA1 a potential marker for the selection of patients best suited for CDK4/6 inhibitor therapy.”

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