Skip to main content
main-content

13.02.2018 | Original Research Article | Ausgabe 2/2018

Targeted Oncology 2/2018

Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines

Zeitschrift:
Targeted Oncology > Ausgabe 2/2018
Autoren:
Valentina Restelli, Monica Lupi, Micaela Vagni, Rosaria Chilà, Francesco Bertoni, Giovanna Damia, Laura Carrassa
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s11523-018-0553-6) contains supplementary material, which is available to authorized users.

Abstract

Background

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton’s tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment.

Objective

To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors.

Methods

We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects.

Results

The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib.

Conclusions

The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro-survival pathways (by ibrutinib) might offer a promising new therapeutic strategy for MCL patients.

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

★ PREMIUM-INHALT
e.Med Interdisziplinär

Mit e.Med Interdisziplinär erhalten Sie Zugang zu allen CME-Fortbildungen und Fachzeitschriften auf SpringerMedizin.de. Zusätzlich können Sie eine Zeitschrift Ihrer Wahl in gedruckter Form beziehen – ohne Aufpreis.

Weitere Produktempfehlungen anzeigen
Zusatzmaterial
ESM 1 (PDF 718 kb)
11523_2018_553_MOESM1_ESM.pdf
Literatur
Über diesen Artikel

Weitere Artikel der Ausgabe 2/2018

Targeted Oncology 2/2018 Zur Ausgabe
  1. Das kostenlose Testabonnement läuft nach 14 Tagen automatisch und formlos aus. Dieses Abonnement kann nur einmal getestet werden.

  2. Das kostenlose Testabonnement läuft nach 14 Tagen automatisch und formlos aus. Dieses Abonnement kann nur einmal getestet werden.

Neu im Fachgebiet Onkologie

Mail Icon II Newsletter

Bestellen Sie unseren kostenlosen Newsletter Update Onkologie und bleiben Sie gut informiert – ganz bequem per eMail.

Bildnachweise