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UNC2025, a MERTK Small-Molecule Inhibitor, Is Therapeutically Effective Alone and in Combination with Methotrexate in Leukemia Models
- Source :
- Clinical Cancer Research. 23:1481-1492
- Publication Year :
- 2017
- Publisher :
- American Association for Cancer Research (AACR), 2017.
-
Abstract
- Purpose: MERTK tyrosine kinase is ectopically expressed in 30% to 50% of acute lymphoblastic leukemias (ALL) and more than 80% of acute myeloid leukemias (AML) and is a potential therapeutic target. Here, we evaluated the utility of UNC2025, a MERTK tyrosine kinase inhibitor, for treatment of acute leukemia. Experimental Design: Preclinical in vitro and in vivo assays using cell lines and primary leukemia patient samples were used to evaluate antileukemic effects of UNC2025. Results: UNC2025 potently inhibited prosurvival signaling, induced apoptosis, and reduced proliferation and colony formation in MERTK-expressing ALL and AML cell lines and patient samples. Approximately 30% of primary leukemia patient samples (78 of 261 total) were sensitive to UNC2025. Sensitive samples were most prevalent in the AML, T-ALL, and minimally differentiated (M0) AML subsets. UNC2025 inhibited MERTK in bone marrow leukemia cells and had significant therapeutic effects in xenograft models, with dose-dependent decreases in tumor burden and consistent two-fold increases in median survival, irrespective of starting disease burden. In a patient-derived AML xenograft model, treatment with UNC2025 induced disease regression. In addition, UNC2025 increased sensitivity to methotrexate in vivo, suggesting that addition of MERTK-targeted therapy to current cytotoxic regimens may be particularly effective and/or allow for chemotherapy dose reduction. Conclusions: The broad-spectrum activity mediated by UNC2025 in leukemia patient samples and xenograft models, alone or in combination with cytotoxic chemotherapy, supports continued development of MERTK inhibitors for treatment of leukemia. Clin Cancer Res; 23(6); 1481–92. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Myeloid
medicine.drug_class
medicine.medical_treatment
Apoptosis
Piperazines
Tyrosine-kinase inhibitor
Mice
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
hemic and lymphatic diseases
Antineoplastic Combined Chemotherapy Protocols
medicine
Animals
Humans
Chemotherapy
c-Mer Tyrosine Kinase
Gene Expression Regulation, Leukemic
business.industry
Adenine
MERTK
medicine.disease
Xenograft Model Antitumor Assays
Leukemia, Myeloid, Acute
Leukemia
Methotrexate
030104 developmental biology
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Immunology
Cancer research
Bone marrow
business
Tyrosine kinase
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 23
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....a16f29d8bba59236391a7e818e345f52