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

Autoři	GLEIXNER K. V. FILIK Y. BERGER D. SCHEWZIK C. STEFANZL G. SADOVNIK I. DEGENFELD-SCHONBURG L. EISENWORT G. SCHNEEWEISS-GLEIXNER M. BYRGAZOV K. SPERR W. R. MAYER Jiří LION T. VALENT P.
Rok publikování	2021
Druh	Článek v odborném periodiku
Časopis / Zdroj	AMERICAN JOURNAL OF CANCER RESEARCH
Fakulta / Pracoviště MU	Lékařská fakulta
Citace
www	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493381/
Klíčová slova	CML; asciminib; ponatinib; BCR-ABL1(T315I); BCR-ABL1 compound mutations; drug combinations; leukemic stem cells; hydroxyurea
Popis	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.