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Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies
- Source :
- Leukemia. 29:27-37
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
Abstract
- Direct targeting of rat sarcoma (RAS), which is frequently mutated, has proven to be challenging, and inhibition of individual downstream RAS mediators has resulted in limited clinical efficacy. We designed a chemical screen to identify compounds capable of potentiating mammalian target of rapamycin (mTOR) inhibition in mutant RAS-positive leukemia, and identified a Wee1 inhibitor. Synergy was observed in both mutant neuroblastoma RAS viral oncogene homolog (NRAS)- and mutant kirsten RAS viral oncogene homolog (KRAS)-positive acute myelogenous leukemia (AML) cell lines and primary patient samples. The observed synergy enhanced dephosphorylation of AKT, 4E-binding protein 1 and s6 kinase, and correlated with increased apoptosis. The specificity of Wee1 as the target of MK-1775 was validated by Wee1 knockdown, as well as partial reversal of drug combination-induced apoptosis by a cyclin-dependent kinase 1 (CDK1) inhibitor. Importantly, we also extended our findings to other mutant RAS-expressing malignancies, including mutant NRAS-positive melanoma, and mutant KRAS-positive colorectal cancer, pancreatic cancer and lung cancer. We observed favorable responses with combined Wee1/mTOR inhibition in human cancer cell lines from multiple malignancies, and inhibition of tumor growth in in vivo models of mutant KRAS lung cancer and leukemia. The present study introduces for the first time Wee1 inhibition combined with mTOR inhibition as a novel therapeutic strategy for the selective treatment of mutant RAS-positive leukemia and other mutant RAS-expressing malignancies.
- Subjects :
- Neuroblastoma RAS viral oncogene homolog
Cancer Research
Antineoplastic Agents
Cell Cycle Proteins
Pyrimidinones
medicine.disease_cause
Article
Proto-Oncogene Proteins p21(ras)
Mice
Cell Line, Tumor
medicine
Animals
RNA, Small Interfering
Protein kinase B
PI3K/AKT/mTOR pathway
Acute leukemia
Base Sequence
biology
Nuclear Proteins
Hematology
Protein-Tyrosine Kinases
medicine.disease
Leukemia, Myeloid, Acute
Wee1
Leukemia
Pyrimidines
Oncology
Gene Knockdown Techniques
biology.protein
Cancer research
Pyrazoles
KRAS
Subjects
Details
- ISSN :
- 14765551 and 08876924
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Leukemia
- Accession number :
- edsair.doi.dedup.....a6051da4c4e42f7cfc3cc9e41ed3e525