Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies

E. Weisberg, Atsushi Nonami, Z. Chen, F. Liu, J. Zhang, M. Sattler, E. Nelson, K. Cowens, A. L. Christie, C. Mitsiades, K. K. Wong, Q. Liu, N. Gray, J. D. Griffin

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 languageEnglish
Pages (from-to)27-37
Number of pages11
JournalLeukemia
Volume29
Issue number1
DOIs
Publication statusPublished - Jan 10 2015
Externally publishedYes

Fingerprint

Sarcoma
Leukemia
Neoplasms
Sirolimus
Lung Neoplasms
Therapeutics
Oncogenes
CDC2 Protein Kinase
Apoptosis
Ribosomal Protein S6 Kinases
Cell Line
Drug Combinations
Neuroblastoma
Pancreatic Neoplasms
Acute Myeloid Leukemia
Protein Kinases
Colorectal Neoplasms
Melanoma
Carrier Proteins
Growth

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 journalArticle

Weisberg, E, Nonami, A, Chen, Z, Liu, F, Zhang, J, Sattler, M, Nelson, E, Cowens, K, Christie, AL, Mitsiades, C, Wong, KK, Liu, Q, Gray, N & Griffin, JD 2015, 'Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies', Leukemia, vol. 29, no. 1, pp. 27-37. https://doi.org/10.1038/leu.2014.149
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. / Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies. In: Leukemia. 2015 ; Vol. 29, No. 1. pp. 27-37.
@article{5870ce8541db470ea9af755dccb95994,
title = "Identification of Wee1 as a novel therapeutic target for mutant RAS-driven acute leukemia and other malignancies",
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.",
author = "E. Weisberg and Atsushi Nonami and Z. Chen and F. Liu and J. Zhang and M. Sattler and E. Nelson and K. Cowens and Christie, {A. L.} and C. Mitsiades and Wong, {K. K.} and Q. Liu and N. Gray and Griffin, {J. D.}",
year = "2015",
month = "1",
day = "10",
doi = "10.1038/leu.2014.149",
language = "English",
volume = "29",
pages = "27--37",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "1",

}

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 -