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 journalArticle

8 Citations (Scopus)

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

Fingerprint

Mantle-Cell Lymphoma
Cell Line
Cyclin D1
S Phase
Genetic Translocation
Foster Home Care
G1 Phase
Gene Expression Profiling
B-Cell Lymphoma
Pharmacology
PF 00477736
Genes
Therapeutics

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736. / Restelli, Valentina; Chilà, Rosaria; Lupi, Monica; Rinaldi, Andrea; Kwee, Ivo; Bertoni, Francesco; Damia, Giovanna; Carrassa, Laura.

In: Oncotarget, Vol. 6, No. 35, 2015, p. 37229-37240.

Research output: Contribution to journalArticle

Restelli, Valentina ; Chilà, Rosaria ; Lupi, Monica ; Rinaldi, Andrea ; Kwee, Ivo ; Bertoni, Francesco ; Damia, Giovanna ; Carrassa, Laura. / Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736. In: Oncotarget. 2015 ; Vol. 6, No. 35. pp. 37229-37240.
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