A new mechanism of resistance to ABL1 tyrosine kinase inhibitors in a BCR-ABL1-positive cell line
| Autor: | Francois-Xavier Mahon, Kelly Airiau, Béatrice Turcq, Francis Belloc |
|---|---|
| Přispěvatelé: | Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research [SDV]Life Sciences [q-bio] Resistance Dasatinib Fusion Proteins bcr-abl Apoptosis Stem cell factor Proto-Oncogene Proteins c-fyn Polymerase Chain Reaction 0302 clinical medicine hemic and lymphatic diseases MESH: Protein Kinase Inhibitors MESH: In Situ Hybridization Fluorescence In Situ Hybridization Fluorescence ABL Chemistry MEK inhibitor Chronic myeloid leukemia MESH: Dasatinib Hematology MESH: Drug Resistance Neoplasm 3. Good health Oncology 030220 oncology & carcinogenesis SRC kinase Tyrosine kinase Proto-oncogene tyrosine-protein kinase Src medicine.drug MAP Kinase Signaling System Blotting Western Antineoplastic Agents 03 medical and health sciences FYN Leukemia Myelogenous Chronic BCR-ABL Positive medicine MESH: Blotting Western Humans Protein Kinase Inhibitors MESH: K562 Cells [SDV.GEN]Life Sciences [q-bio]/Genetics MESH: Humans MESH: MAP Kinase Signaling System Cell growth MESH: Apoptosis MESH: Fusion Proteins bcr-abl MESH: Polymerase Chain Reaction MESH: Proto-Oncogene Proteins c-fyn 030104 developmental biology MESH: Leukemia Myelogenous Chronic BCR-ABL Positive Drug Resistance Neoplasm Immunology Cancer research MESH: Antineoplastic Agents K562 Cells MEK/ERK |
| Zdroj: | Leukemia Research Leukemia Research, Elsevier, 2017, 61, pp.44-52. ⟨10.1016/j.leukres.2017.08.014⟩ |
| ISSN: | 0145-2126 |
| DOI: | 10.1016/j.leukres.2017.08.014 |
| Popis: | International audience; Tyrosine kinase inhibitors (TKI) constitute the frontline treatment for chronic myeloid leukemia patients. Dasatinib, a second-generation TKI, was developed to overcome TKI resistances. However, dasatinib resistances are also described but remain less characterized. To mimic in vivo acquired dasatinib resistance, the BCR-ABL1-positive cell line K562 was transiently treated with a pharmacological concentration of dasatinib, for a short time in the presence of stem cell factor. A dasatinib resistant counterpart (K562 RES) was developed. Investigation of resistance mechanisms using kinase substrate arrays revealed that FYN was overactivated in K562 RES. The FYN inhibitor KX2-391 cooperated with dasatinib to block K562 RES proliferation. Cell tracking experiments showed that activated FYN support cell proliferation independently of BCR-ABL1 in K562 RES cells. Moreover, the MEK-ERK pathway was found hyper-phosphorylated in K562 RES cells even in the presence of dasatinib. Actually, ERK1/2 activity supported viability in K562 RES only in the absence of BCR-ABL1 activity. Finally, BCR-ABL1 and MEK inhibitor combination was sufficient to induce cell death even in non-proliferating resistant cells. Considering the conditions used to generate this dasatinib resistant cell line, such a resistance mechanism could be found in dasatinib treated patients. Consequently, it is valuable to know that inhibition of the MEK-ERK1/2 axis can overcome this resistance. |
| Databáze: | OpenAIRE |
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