Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1(T315I)-compound mutations

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.

Automated summary

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.