title: Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma.
abstract: Mantle cell lymphoma (MCL) is an aggressive, incurable disease, characterized by a deregulated cell cycle. Chk1 and Wee1 are main regulators of cell cycle progression and recent data on solid tumors suggest that simultaneous inhibition of these proteins has a strong synergistic cytotoxic effect. The effects of a Chk1 inhibitor (PF-00477736) and a Wee1 inhibitor (MK-1775) have been herein investigated in a large panel of mature B-cell lymphoma cell lines. We found that MCL cells were the most sensitive to the Chk1 inhibitor PF-00477736 and Wee1 inhibitor MK-1775 as single agents. Possible involvement of the translocation t(11;14) in Chk1 inhibitor sensitivity was hypothesized. The combined inhibition of Chk1 and Wee1 was strongly synergistic in MCL cells, leading to deregulation of the cell cycle, with increased activity of CDK2 and CDK1, and activation of apoptosis. In vivo treatment with the drug combination of mice bearing JeKo-1 xenografts (MCL) had a marked antitumor effect with tumor regressions observed at non-toxic doses (best T/C%=0.54%). Gene expression profiling suggested effect on genes involved in apoptosis. The strong synergism observed by combining Chk1 and Wee1 inhibitors in preclinical models of MCL provides the rationale for testing this combination in the clinical setting.
authors.affiliation: Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Chilà
authors.affiliation: Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Basana
authors.affiliation: Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Lupi
authors.affiliation: Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Guffanti
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.affiliation: Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Restelli
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Tarantelli
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland.|Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bertoni
authors.affiliation: Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Damia
authors.affiliation: Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Carrassa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001570:Benzodiazepinones / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D020128:Inhibitory Concentration 50; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001570:Benzodiazepinones; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C532366:PF 00477736; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C549567:adavosertib