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Inhibiting the LSD1 enzyme renders some leukemia cells sensitive to TKI treatment

Science Signaling
Reuters Health -  25/04/2022 - A laboratory study suggests that inhibition of LSD1 (lysine-specific demethylase) renders some patient-derived acute myeloid leukemia (AML) cells sensitive to the MEK inhibitor trametinib.

Typically, AML is resistant to tyrosine kinase inhibitors such trametinib.

"We know that resistance often happens because there are several biochemical pathways in cancer cells that can compensate for the inhibition of a given kinase," Dr. Pedro Cutillas of Queen Mary University of London, UK, told Reuters Health by email. "We wanted to use this knowledge to identify ways to remodel the biology of cancer so that previously resistant cancer cells could become sensitive to treatment."

The team found that LSD1 inhibitors increase the activity of MEK, which is trametinib's target, "while dampening compensatory pathways," he explained. "Thus, cancer cells can no longer compensate for MEK inhibition and die when treated with the LSD1 inhibitor followed by the MEK inhibitor."

"Not all patient samples responded to this treatment," he added, "but we identified the biomarkers that predict patients that may respond best."

Working in cultured AML cells, Dr. Cutillas and colleagues report in Science Signaling that they identified several antagonists of chromatin-modifying enzymes that sensitized AML cell lines to kinase inhibitors. Of these, LSD1 - also known as KDM1A - rewired kinase signaling in the cells in a way that increased MEK activity and broadly suppressed the activity of other kinases.

Sequential treatment with the LSD1 inhibitor followed by the MEK inhibitor primed AML cell lines and about half of primary human AML samples for sensitivity to trametinib, and increased apoptosis. By contrast, healthy hematopoietic cells were not affected.

Primary human cells with KRAS mutations and those with high MEK pathway activity were the best responders; in contrast, cells with NRAS mutations and high mTOR activity were poor responders.

The authors write, "Overall, our study reveals the MEK pathway as a mechanism of resistance to LSD1 inhibitors in AML and shows a way to modulate kinase network circuitry to potentially overcome therapeutic resistance to kinase inhibitors."

Commenting on the study, Dr. David Taussig, a consultant hematologist at The Royal Marsden and a team leader at the Institute of Cancer Research, London, called the approach "promising."

"Prior attempts to inhibit apparently key signaling pathways in leukemia cells have frequently been unsuccessful in patients with AML," he said by email. "Even where drugs are initially successful, AML evolves mutations in other pathways to overcome the action of inhibitors."

"The caveats, which the authors acknowledge, are that this work is based on in vitro data and that this needs confirming in vivo (pre-clinical models) and in patients," he said.

"One strength of the work is that they study the effects on both AML and normal hematopoietic cells that compete for the same marrow space," he noted. "Killing off both leukemia and normal hematopoiesis would cause patients to suffer from marrow failure. Establishing a treatment that is relatively selective for AML is important to avoid this toxicity."

"Simultaneous treatment of AML cells by LSD1-inhibitors and the kinase inhibitors was less effective than the sequential treatment," he said. "I would like to see how much pre-treatment with LSD1-inhibitors is required in vivo before the kinase inhibitors are added."

SOURCE: https://bit.ly/3ES6rhF Science Signaling, online April 19, 2022.

By Marilynn Larkin

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