LSD1 inhibition sensitizes AML cells to MAPK inhibitor

May 2022 Medical Research Nalinee Pathak

Scientists from Barts Cancer Institute at the Queen Mary University of London reported that blocking LSD1 (an enzyme) sensitises leukaemia cells to kinase inhibitors. The findings from this study were recently published in the journal Science Signalling.

One of the main characteristic features associated with cancers is the dysregulation of signalling pathways such as PI3K, MAPK etc. Thus, targeting kinases (enzymes regulating these pathways) form an attractive therapeutic strategy for targeting cancer cells.  There are several inhibitors available against a wide array of kinases. Although patients respond to these inhibitors, many develop resistance, resulting in disease relapse. Therefore, identify ways to overcome kinase inhibitor resistance in cancers.

Professor Pedro Cutillas and co have found a way to overcome kinase inhibitor resistance in leukaemia cells. The group found that targeting a chromatin-modifying enzyme LSD1 (GSK2879552) rewired kinase signalling in acute myeloid leukaemia (AML) cell lines. LSD1 inhibited the PI3Kinase pathway but activated another kinase pathway, MAPK. Thus, a second inhibitor, trametinib (MAPK inhibitor) after LSD1 inhibitor, was lethal to AML cells.

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 study’s findings indicate that rather than using two drugs together, using a sequential treatment strategy would be more efficient. The first drug makes cancer cells more dependent on one specific pathway, which can further be targeted for getting optimal results.

Reference

Pedicona F, Casado P, Hijazi M, Gribben JG, et al. Targeting the lysine-specific demethylase 1 rewires kinase networks and primes leukemia cells for kinase inhibitor treatment. Sci Signal. 2022 Apr 19;15(730):eabl7989. doi: 10.1126/scisignal.abl7989. Epub 2022 Apr 19.

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