Overcoming Resistance To MTOR Inhibitors In Acute Myeloid Leukemia

Rapamycin is the first mTOR inhibitor that targets unwanted cell proliferation. Cancer experts believe that drugs targeting mTOR would become a breakthrough targeted therapy for children and adults suffering relapses of acute myeloid leukemia (AML) and other cancers where mTOR activity is abnormally high. Various clinical trials involving three generations of mTOR inhibitors have found that cancer cells have a remarkable ability to make new cells that dodge these drugs. Due to this, some people with AML treated with mTOR inhibitors develop fatal relapses despite so many improvements in leukemia outcomes over the years.

Yi Zheng, PhD Director, Experimental Hematology and Cancer Biology at Cincinnati Children's said, “Overcoming resistance to therapy remains a holy grail of leukemia treatment. While mTOR is a recognized target for AML and many cancers, inhibitor trials have not gone as expected."

The research led by Zheng and colleagues at Cincinnati Children's is published in the journal PNAS

They have found a novel method to boost the effectiveness of mTOR inhibitors, eventually leading to improved outcomes for patients with AML and possibly other forms of cancer.

mTOR inhibitors Trigger An Alarm

The protein mTOR is involved in regulating survival, cell growth, metabolism, and immunity and any disturbance to the normal mTOR activity can lead to several types of cancer and other conditions. Hence many scientist have conducted research on this mTOR signaling pathway.

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Senior author of the study, Yi Zheng said, “Using a novel mouse model, we have learned that deleting the mTOR gene prompts blood stem cells to multiply rapidly to open other pathways to continue producing new blood cells. We also found that leukemia cells use a similar response to continue multiplying despite mTOR-inhibiting treatments.”

Targeting mTOR triggers off alarms in the hemopoietic stem cells (HSCs) that produce blood cells in the bone marrow resulting in hyperproliferation of the blood cells that produces a flood of new, re-wired blood cells.

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In the same manner, re-wired cancer stem cells treated with mTOR inhibitors begin multiplying by using a new signaling pathway instead of mTOR resulting in cancer cells resistant to mTOR inhibitors.

Overcoming Resistance

The researchers figured out how blood stem cells in mice re-wire themselves when mTOR gene activity is deleted by using a combination of genetic analysis tools like RNA-seq, ChIP-seq, and ATAC-seq. They found that HSCs respond to the loss of mTOR by activating the ERK/MNK/eIF4E signaling pathway that enhances the protein translation of RNA polymerase II, which boosts the expression of gene c-Myc that that allows both normal HSCs and leukemic stem cells to survive.

However, some drugs are already available that work against this alternate signaling pathway suggesting that a combination therapy could use an mTOR inhibitor to directly attack AML cell production while using other drugs to cut off alternative production paths.

The researchers state that resistance to mTOR can be overcomed by blocking the activity of the MNK gene, CDK9, or c-Myc. Few other drugs available include BET inhibitors and CDK9 which are currently in clinical trials.

The researchers have started preparing for clinical trials though it will require some time. As mTOR has been recognized as a target in most human cancers, including solid tumors like brain tumors, the findings may extend beyond AML.

Source-Medindia