Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736
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Valentina Restelli1, Rosaria Chilà1, Monica Lupi1, Andrea Rinaldi2, Ivo Kwee2,3,4, Francesco Bertoni2,5, Giovanna Damia1 and Laura Carrassa1
1 Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS- Istituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy
2 Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland
3 Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno, Switzerland
4 Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland
5 Lymphoma Unit, IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
Laura Carrassa, email:
Giovanna Damia, email:
Keywords: Chk1, cyclin D1, mantle cell lymphoma, targeted therapy, mechanisms of resistance
Received: June 17, 2015 Accepted: September 17, 2015 Published: October 02, 2015
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.
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