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.
Keywords:
Chk1; cyclin D1; mantle cell lymphoma; mechanisms of resistance; targeted therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Benzodiazepinones / pharmacology*
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Cell Cycle / drug effects*
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Checkpoint Kinase 1
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Dasatinib / pharmacology
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Dose-Response Relationship, Drug
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Drug Resistance, Neoplasm* / drug effects
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Humans
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Lymphoma, Mantle-Cell / drug therapy*
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Lymphoma, Mantle-Cell / enzymology
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Lymphoma, Mantle-Cell / genetics
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Lymphoma, Mantle-Cell / pathology
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Molecular Targeted Therapy
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinases / metabolism*
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Pyrazoles / pharmacology*
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Pyrimidines / pharmacology
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Pyrimidinones
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Signal Transduction / drug effects
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Thiophenes / pharmacology
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Time Factors
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Urea / analogs & derivatives
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Urea / pharmacology
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / metabolism
Substances
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3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
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Antineoplastic Agents
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Benzodiazepinones
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CCND1 protein, human
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Cell Cycle Proteins
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Nuclear Proteins
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PF 00477736
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Pyrimidinones
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Thiophenes
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Cyclin D1
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Urea
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Protein Kinases
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Protein-Tyrosine Kinases
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WEE1 protein, human
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src-Family Kinases
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CHEK1 protein, human
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Checkpoint Kinase 1
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adavosertib
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Dasatinib