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.
| Original language | English |
|---|---|
| Pages (from-to) | 27-37 |
| Number of pages | 11 |
| Journal | Leukemia |
| Volume | 29 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 10 2015 |
| Externally published | Yes |
Fingerprint
All Science Journal Classification (ASJC) codes
- Hematology
- Oncology
- Cancer Research
Cite this
Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies. / Weisberg, E.; Nonami, Atsushi; Chen, Z.; Liu, F.; Zhang, J.; Sattler, M.; Nelson, E.; Cowens, K.; Christie, A. L.; Mitsiades, C.; Wong, K. K.; Liu, Q.; Gray, N.; Griffin, J. D.
In: Leukemia, Vol. 29, No. 1, 10.01.2015, p. 27-37.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies
AU - Weisberg, E.
AU - Nonami, Atsushi
AU - Chen, Z.
AU - Liu, F.
AU - Zhang, J.
AU - Sattler, M.
AU - Nelson, E.
AU - Cowens, K.
AU - Christie, A. L.
AU - Mitsiades, C.
AU - Wong, K. K.
AU - Liu, Q.
AU - Gray, N.
AU - Griffin, J. D.
PY - 2015/1/10
Y1 - 2015/1/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84920641027&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920641027&partnerID=8YFLogxK
U2 - 10.1038/leu.2014.149
DO - 10.1038/leu.2014.149
M3 - Article
VL - 29
SP - 27
EP - 37
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 1
ER -