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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F21%3A00075855" target="_blank" >RIV/65269705:_____/21:00075855 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14110/21:00124159

Result on the web

<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493398/pdf/ajcr0011-4470.pdf" target="_blank" >https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493398/pdf/ajcr0011-4470.pdf</a>

DOI - Digital Object Identifier

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Result language

angličtina

Original language name

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

Original language description

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 &apos;asciminib+ponatinib&apos; 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 &apos;asciminib+ponatinib&apos; and &apos;asciminib+ponatinib+HU&apos; 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30204 - Oncology

Project

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Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2021

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

American Journal of Cancer Research

ISSN

2156-6976

e-ISSN

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Volume of the periodical

11

Issue of the periodical within the volume

9

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

4470-4484

UT code for WoS article

000707716300025

EID of the result in the Scopus database

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