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: Valentina Restelli, Rosaria Chilà, Monica Lupi, Andrea Rinaldi, Ivo Kwee, Francesco Bertoni, Giovanna Damia, Laura Carrassa
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 35 Pg. 37229-40 (Nov 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26439697 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• Antineoplastic Agents
• Benzodiazepinones
• CCND1 protein, human
• Cell Cycle Proteins
• Nuclear Proteins
• PF 00477736
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Pyrimidinones
• Thiophenes
• Cyclin D1
• Urea
• Protein Kinases
• Protein-Tyrosine Kinases
• WEE1 protein, human
• src-Family Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• adavosertib
• Dasatinib

Topics

• Antineoplastic Agents (pharmacology)
• Benzodiazepinones (pharmacology)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (antagonists & inhibitors, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Checkpoint Kinase 1
• Cyclin D1 (genetics, metabolism)
• Dasatinib (pharmacology)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Lymphoma, Mantle-Cell (drug therapy, enzymology, genetics, pathology)
• Molecular Targeted Therapy
• Nuclear Proteins (antagonists & inhibitors, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (metabolism)
• Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Pyrimidinones
• Signal Transduction (drug effects)
• Thiophenes (pharmacology)
• Time Factors
• Urea (analogs & derivatives, pharmacology)
• src-Family Kinases (antagonists & inhibitors, metabolism)