Journal
AMERICAN JOURNAL OF CANCER RESEARCH
Volume 11, Issue 9, Pages 4470-4484Publisher
E-CENTURY PUBLISHING CORP
Keywords
CML; asciminib; ponatinib; BCR-ABL1(T315I); BCR-ABL1 compound mutations; drug combinations; leukemic stem cells; hydroxyurea
Categories
Funding
- Austrian Science Fund (FWF) [F4701, F4704]
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Research shows that the combination of asciminib and ponatinib has a synergistic effect on inducing apoptosis in CML cells, especially effective against cells with T315I+ BCR-ABL1 compound mutations, with further enhanced anti-leukemic effects when used in combination with HU.
Ponatinib is a tyrosine kinase inhibitor (TKI) directed against BCR-ABL1 which is successfully used in patients with BCR-ABL1(T315I)+ chronic myeloid leukemia (CML). However, BCR- ABL1 compound mutations may develop during therapy in these patients and may lead to drug resistance. Asciminib is a novel drug capable of targeting most BCR-ABL1 mutant-forms, including BCR- ABL1(T315I), but remains ineffective against most BCR-ABL1(T315I)+ compound mutation-bearing sub-clones. We demonstrate that asciminib synergizes with ponatinib in inducing growth-arrest and apoptosis in patient-derived CML cell lines and murine Ba/F3 cells harboring BCR-ABL1(T315I) or T315I-including compound mutations. Asciminib and ponatinib also produced cooperative effects on CRKL phosphorylation in BCR-ABL1-transformed cells. The growth-inhibitory effects of the drug combination 'asciminib+ponatinib' was further enhanced by hydroxyurea (HU), a drug which has lately been described to suppresses the proliferation of BCRABL1(T315I)+ CML cells. Cooperative drug effects were also observed in patient-derived CML cells. Most importantly, we were able to show that the combinations `asciminib+ponatinib' and `asciminib+ponatinib+HU' produce synergistic apoptosis-inducing effects in CD34(+)/CD38(-) CML stem cells obtained from patients with chronic phase CML or BCR-ABL1(T315I)+ CML blast phase. Together, asciminib, ponatinib and HU synergize in producing anti-leukemic effects in multi-resistant CML cells, including cells harboring T315I+ BCR-ABL1 compound mutations and CML stem cells. The clinical efficacy of this TKI combination needs to be evaluated within the frame of upcoming clinical trials.
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