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.
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Nonami
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
authors.forename: Feiyang
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston Massachusetts, USA.
authors.forename: Jianming
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Sattler
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Nelson
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Cowens
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: High Magnetic Field laboratory, Chinese Academy of Sciences, Hefei, Anhui, P. R. China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston Massachusetts, USA.
authors.forename: Nathanael
authors.initials: N
authors.lastname: Gray
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D009687:Nuclear Proteins / Q000187:drug effects* / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016283:Proto-Oncogene Proteins p21(ras); C549567:adavosertib