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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216224:14110/21:00124159

Výsledek na webu

<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

—

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30204 - Oncology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

American Journal of Cancer Research

ISSN

2156-6976

e-ISSN

—

Svazek periodika

11

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

4470-4484

Kód UT WoS článku

000707716300025

EID výsledku v databázi Scopus

—