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

GLEIXNER, K. V., Y. FILIK, D. BERGER, C. SCHEWZIK, G. STEFANZL, I. SADOVNIK, L. DEGENFELD-SCHONBURG, G. EISENWORT, M. SCHNEEWEISS-GLEIXNER, K. BYRGAZOV, W. R. SPERR, Jiří MAYER, T. LION and P. VALENT. Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1(T315I)-compound mutations. AMERICAN JOURNAL OF CANCER RESEARCH. MADISON: E-CENTURY PUBLISHING CORP, 2021, vol. 11, No 9, p. 4470-4484. ISSN 2156-6976.

Basic information

• Original name: Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1(T315I)-compound mutations
• Authors: GLEIXNER, K. V. (guarantor), Y. FILIK, D. BERGER, C. SCHEWZIK, G. STEFANZL, I. SADOVNIK, L. DEGENFELD-SCHONBURG, G. EISENWORT, M. SCHNEEWEISS-GLEIXNER, K. BYRGAZOV, W. R. SPERR, Jiří MAYER (203 Czech Republic, belonging to the institution), T. LION and P. VALENT.
• Edition: AMERICAN JOURNAL OF CANCER RESEARCH, MADISON, E-CENTURY PUBLISHING CORP, 2021, 2156-6976.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30204 Oncology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 5.942
• RIV identification code: RIV/00216224:14110/21:00124159
• Organization unit: Faculty of Medicine
• UT WoS: 000707716300025
• Keywords in English: CML; asciminib; ponatinib; BCR-ABL1(T315I); BCR-ABL1 compound mutations; drug combinations; leukemic stem cells; hydroxyurea
• Tags: 14110212, rivok
• Tags: International impact, Reviewed

Abstract

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.