06 May 2022

A UK team have identified a way to reverse resistance to kinase inhibitors in acute myeloid leukaemia (AML) cells.

In the laboratory, a team from Barts Cancer Institute at Queen Mary University of London ‘rewired’ the inner workings of the cancer cells to prime leukaemia cells for sensitivity to kinase inhibitors.

Kinase inhibitors block components of different signalling pathways that cancer cells use to grow and survive and have had some success in the treatment of some tumour types.

However, many cancers fail to respond to or develop resistance against these targeted drugs. This is because cells can learn to use other routes to carry out a function when a drug blocks their usual pathway. This intrinsic resistance compensates for the effects of the drug and can prevent the drug from killing the cancer cell.

For this study, the team led by Professor Pedro Cutillas found that manipulating the cellular pathways the cells use to survive could overcome kinase inhibitor resistance in leukaemia cells. Their study builds on previous work that investigated the mechanisms of resistance to drugs that target kinases.

The team first treated leukaemia cell lines with GSK2879552, an experimental drug to block the LSD1 enzyme, which helps to control gene expression in cells.

Blocking LSD1 inhibited the activity of the PI3K/AKT pathway but activated the MEK/MAPK pathway that the leukaemia cells had to use to survive.

With the leukaemia cells relying on the MEK/MAPK pathway for survival, the team used trametinib, a MEK inhibitor, to block the pathway again and cut off all escape routes for the cells.

The findings are published in the latest edition of Science Signaling.

Study lead Professor Cutillas, from BCI’s Centre for Cancer Genomics & Computational Biology, said: “Here, we found that intrinsic resistance to kinase inhibitors could be overcome by coercing kinase networks into pathways that are tolerant to drug sensitivity.

“By targeting LSD1 with a drug, we rewired the kinase network and left cancer cells unable to escape from treatment with the second drug, trametinib.”

The researchers used the same sequential treatment approach to treat blood cells collected from patients with acute myeloid leukaemia (AML) and found the drug regimen killed about half of the AML samples.

Certain genetic changes and characteristics within the cancer cells influenced if the cells were sensitive or resistant to the sequential treatment. These could represent biomarkers that could help to predict the subpopulation of patients who are more likely to respond to this kind of treatment.

Early phase clinical trials have shown that trametinib has limited efficacy against leukaemia, but these studies identified a way in which drug resistance to these kinase inhibitors may be reversed and potentially avoided.

Prof Cutillas said: “Instead of treating cancers with two or more drugs at the same time, as has been the main approach in previous research on drug combinations, our work suggests that sequential treatment with one inhibitor to create a new pathway dependency, followed by treatment with an inhibitor against the newly activated pathway may be an effective treatment strategy in leukaemia.”

Source: Pedicona F, Casado P, Hijazi M, Gribben JG, Rouault-Pierre K, Cutillas PR. (2022) “Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment.” Science Signaling, doi: 10.1126/scisignal.abl7989

Link: https://www.science.org/doi/10.1126/scisignal.abl7989

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