18 January 2021

Scientists have uncovered a mechanism by which acute myeloid leukaemia (AML) cells develop drug resistance.

Some patients who are given drugs like rapamycin, called mTOR inhibitors, experience fatal relapse because cancer cells find ways to dodge the treatment and make new resistant cancer, the researchers say.

But a new discovery opens up new avenues for combination drug treatments that could block the escape routes the leukaemia cells use.

The study led by Dr Yi Zheng of Cincinnati Children's Hospital Medical Center, USA, used mice to study how cells adapt when they can no longer use the mTOR molecule.

They found that deleting the mTOR gene in mice causes blood stem cells to use alternative pathways to continue producing new blood cells. They found that leukaemia cells use a similar response to continue multiplying despite mTOR-blocking treatments.

Their findings were published in Proceedings of the National Academy of Sciences.

Dr Zheng explains: "Overcoming resistance to therapy remains a holy grail of leukaemia treatment. While mTOR is a recognised target for acute myeloid leukaemia and many cancers, inhibitor trials have not gone as expected."

He adds that attacking mTOR “essentially sets off alarms among haematopoietic stem cells, which act like blood cell factories deep in bone marrow”. The stem cells then “hyperproliferate”, which produces a flood of new, re-wired blood cells.

In a similar way, cancer stem cells treated with mTOR inhibitors can also begin using new signalling pathways instead of mTOR to multiply, making mTOR inhibitors ineffective.

There are already some drugs in clinical trials that inhibit this alternate signalling pathway, say the authors, such as drugs that inhibit activity of MNK, CDK9 or c-Myc. This possibility will be tested by the researchers, who add that the findings may extend beyond AML to many other human cancers.

Source: Fan C, Zhao C, Zhang F, Kesarwani M, Tu Z, Cai X, Davis AK, Xu L, Hochstetler CL, Chen X, Guo F, Huang G, Azam M, Tian W, Lu QR, Zheng Y. (2021) “Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition.” Proc Natl Acad Sci U S A doi: 10.1073/pnas.2020102118.

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