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

J 2021

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 et. al.

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

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

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

Abstract

V originále

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.

Citovat

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.

@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 and 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, vol.~11, No~9, p.~4470-4484. ISSN~2156-6976.

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