Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736

Valentina Restelli, Rosaria Chilà, Monica Lupi, Andrea Rinaldi, Ivo Kwee, Francesco Bertoni, Giovanna Damia, Laura Carrassa

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)37229-37240
Number of pages12
JournalOncotarget
Volume6
Issue number35
DOIs
Publication statusPublished - 2015

Keywords

  • Chk1
  • Cyclin D1
  • Mantle cell lymphoma
  • Mechanisms of resistance
  • Targeted therapy

ASJC Scopus subject areas

  • Oncology

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