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 a 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, roč. 11, č. 9, s. 4470-4484. ISSN 2156-6976. |
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@article{1834329, author = {Gleixner, K. V. and Filik, Y. and Berger, D. and Schewzik, C. and Stefanzl, G. and Sadovnik, I. and DegenfeldandSchonburg, L. and Eisenwort, G. and SchneeweissandGleixner, M. and Byrgazov, K. and Sperr, W. R. and Mayer, Jiří and Lion, T. and Valent, P.}, article_location = {MADISON}, article_number = {9}, keywords = {CML; asciminib; ponatinib; BCR-ABL1(T315I); BCR-ABL1 compound mutations; drug combinations; leukemic stem cells; hydroxyurea}, language = {eng}, issn = {2156-6976}, journal = {AMERICAN JOURNAL OF CANCER RESEARCH}, title = {Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1(T315I)-compound mutations}, url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493381/}, volume = {11}, year = {2021} }
TY - JOUR ID - 1834329 AU - 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. PY - 2021 TI - Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1(T315I)-compound mutations JF - AMERICAN JOURNAL OF CANCER RESEARCH VL - 11 IS - 9 SP - 4470-4484 EP - 4470-4484 PB - E-CENTURY PUBLISHING CORP SN - 21566976 KW - CML KW - asciminib KW - ponatinib KW - BCR-ABL1(T315I) KW - BCR-ABL1 compound mutations KW - drug combinations KW - leukemic stem cells KW - hydroxyurea UR - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493381/ N2 - 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. ER -
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 a P. VALENT. Asciminib and ponatinib exert synergistic anti-neoplastic effects on CML cells expressing BCR-ABL1(T315I)-compound mutations. \textit{AMERICAN JOURNAL OF CANCER RESEARCH}. MADISON: E-CENTURY PUBLISHING CORP, 2021, roč.~11, č.~9, s.~4470-4484. ISSN~2156-6976.
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