Distinct and overlapping mechanisms of resistance to azacytidine and guadecitabine in acute myeloid leukemia

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Cytosine analogue hypomethylating agents (HMAs) constitute one of the few approved life-prolonging therapies for myelodysplasia (MDS) and acute myeloid leukemia (AML) in patients who are ineligible for intensive chemotherapy. However, single-agent HMAs are not curative, with intrinsic and acquired resistance inevitably leading to treatment failure. Understanding the molecular mechanisms that underpin HMA resistance will enable patient stratification and facilitate the development of rational combination therapies that could be applied concurrently or sequentially. 

We used unbiased genome-wide CRISPR/Cas9 screening methodology and identified rate-limiting enzymes and transporters that mediate resistance to chemically distinct HMAs, azacitidine and guadecitabine. Our data suggest that alternating HMAs may benefit a subset of patients that become refractory following an initial response. Although successful salvage by switching HMA chemotype has been reported, to our knowledge no prospective clinical studies have sought to address this question directly. We believe that our manuscript, along with others in pre-clinical models now lays the ground work to ensure that such studies can be appropriately powered to identify patients that are most likely to benefit from such a strategy.

The work was led in the lab by Emily Gruber, a very talented PhD student who is about to submit her thesis. We had terrific support from Ricky Johnstone and Jake Shortt, as well as great collaborative discussions with Yogen Saunthararajah whose team is tackling similar questions using different methodology. We hope you enjoy reading the paper and welcome any feedback and suggestions you may have.

Lev Kats

Group Leader, Peter MacCallum Cancer Centre

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