Novel treatment strategy targets treatment-resistant CML

Researchers have shown that the coiled-coil (CC) mimetic CCmut3 can inhibit cell growth and promote apoptosis in cell lines expressing BCR–ABL1, including those resistant to tyrosine kinase inhibitors (TKIs).

The findings suggest that the strategy, which disrupts the dimerisation of BCR–ABL1, could lead to new therapies for treatment-resistant chronic myeloid leukaemia (CML).

The research team from the University of Utah in Salt Lake City, USA, used a lentivirus to introduce CCmut3 into a mouse cell line expressing native BCR–ABL1. Compared with control cells infected with an empty vector, these cells showed decreased proliferation and colony formation, and increased apoptosis. Meanwhile, CCmut3 expression had no measurable toxicity in cells that did not express BCR–ABL1.

The researchers then tested CCmut3 in cells expressing mutated forms of BCR–ABL1 – two cell lines with one mutation each in the kinase domain, and a further cell line harbouring both mutations. In the single-mutant cell lines, the authors found a significant inhibition of growth and viability as well as a more than fivefold increase in apoptosis.

In the compound-mutant cells, which are resistant to ponatinib, CCmut3 significantly increased apoptosis and reduced colony formation in comparison to control cells. It also had a significant, but less pronounced, effect on cell proliferation.

Using samples taken from newly diagnosed CML patients, the team also infected CD34+ cells with lentivirus-expressing CCmut3. This resulted in a more than twofold reduction in cell growth, significantly greater than that seen in cells treated with imatinib, and a significant reduction in colony formation.

Additionally, using samples from a ponatinib-treated patient, the researchers showed that CCmut3 had activity in cells expressing mutant BCR–ABL1, even after the development of ponatinib insensitivity.

CML therapy has generally focused on targeting the BCR–ABL1 catalytic site but mutations in the kinase domain can block drug binding, resulting in treatment resistance. By contrast, CCmut3 targets the dimerisation site which, when blocked, prevents the formation of an active BCR–ABL1 kinase, the team explained.

Researcher Carol Lim and colleagues write: “Although all TKIs currently act directly on the kinase domain, we demonstrate that alternative mechanisms of BCR-ABL1 inhibition can circumvent mutation-driven TKI resistance.”

Reporting in Leukemia, the authors say that they intend to explore the development of their therapy as a stapled peptide, in order to try to overcome some of the drug delivery challenges of using peptides.

They also speculate that adding a leukaemia-specific cell-penetrating peptide motif might allow the peptide to target CML stem cells.

“Combination of BCR-ABL1 inhibition by CCmut3 along with inhibition of stem cell survival or self-renewal pathways may result in robust eradication of the CML stem cell”, the researchers suggest.

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Kirsty Oswald

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Kirsty Oswald

Kirsty has a B.Sc. in Human Sciences from University College London. After several years working as medical copywriter, she became a medical journalist and is now freelance. Kirsty also works part-time as an editor for a London-based charity. She is particularly interested in the social and cultural aspects of science.

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