title: Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736.
abstract: Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by the chromosomal translocation t(11;14) that leads to constitutive expression of cyclin D1, a master regulator of the G1-S phase. Chk1 inhibitors have been recently shown to be strongly effective as single agents in MCL. To investigate molecular mechanisms at the basis of Chk1 inhibitor activity, a MCL cell line resistant to the Chk1 inhibitor PF-00477736 (JEKO-1 R) was obtained and characterized. The JEKO-1 R cell line was cross resistant to another Chk1 inhibitor (AZD-7762) and to the Wee1 inhibitor MK-1775. It displayed a shorter doubling time than parental cell line, likely due to a faster S phase. Cyclin D1 expression levels were decreased in resistant cell line and its re-overexpression partially re-established PF-00477736 sensitivity. Gene expression profiling showed an enrichment in gene sets involved in pro-survival pathways in JEKO-1 R. Dasatinib treatment partly restored PF-00477736 sensitivity in resistant cells suggesting that the pharmacological interference of pro-survival pathways can overcome the resistance to Chk1 inhibitors. These data further corroborate the involvement of the t(11;14) in cellular sensitivity to Chk1 inhibitors, fostering the clinical testing of Chk1 inhibitors as single agents in MCL.
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: 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: Monica
authors.initials: M
authors.lastname: Lupi
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.|Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland.|Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
authors.forename: Ivo
authors.initials: I
authors.lastname: Kwee
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: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011744:Pyrimidinones; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D000970:Antineoplastic Agents; D001570:Benzodiazepinones; C530104:CCND1 protein, human; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C532366:PF 00477736; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D013876:Thiophenes; D019938:Cyclin D1; D014508:Urea; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D019061:src-Family Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C549567:adavosertib; D000069439:Dasatinib
keywords: Chk1; cyclin D1; mantle cell lymphoma; mechanisms of resistance; targeted therapy