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Concurrent Inhibition of Akt and ERK Using TIC-10 Can Overcome Venetoclax Resistance in Mantle Cell Lymphoma

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

DOI

  • Agnete Marie Granau, Københavns Universitet
    • ,
  • Pilar Aarøe Andersen, Københavns Universitet
    • ,
  • Theresa Jakobsen
  • Konstantina Taouxi, Københavns Universitet
    • ,
  • Nawar Dalila, Københavns Universitet
    • ,
  • Johanne Bay Mogensen, Københavns Universitet
    • ,
  • Lasse Sommer Kristensen
  • Kirsten Grønbæk, Københavns Universitet, Novo Nordisk Foundation Center for Stem Cell Biology
    • ,
  • Konstantinos Dimopoulos, Københavns Universitet

Venetoclax, a BCL-2 inhibitor, has proven to be effective in several hematological malignancies, including mantle cell lymphoma (MCL). However, development of venetoclax resistance is inevitable and understanding its underlying molecular mechanisms can optimize treatment response. We performed a thorough genetic, epigenetic and transcriptomic analysis of venetoclax-sensitive and resistant MCL cell lines, also evaluating the role of the stromal microenvironment using human and murine co-cultures. In our model, venetoclax resistance was associated with abrogated TP53 activity through an acquired mutation and transcriptional downregulation leading to a diminished apoptotic response. Venetoclax-resistant cells also exhibited an upregulation of the PI3K/Akt pathway, and pharmacological inhibition of Akt and ERK with TIC-10 led to cell death in all venetoclax-resistant cell lines. Overall, we highlight the importance of targeted therapies, such as TIC-10, against venetoclax resistance-related pathways, which might represent future therapeutic prospects.

OriginalsprogEngelsk
Artikelnummer510
TidsskriftCancers
Vol/bind15
Nummer2
ISSN2072-6694
DOI
StatusUdgivet - jan. 2023

Bibliografisk note

Funding Information:
K.G. has received an unrestricted research grant from Janssen Pharma. All other authors have no potential conflict of interest to declare.

Funding Information:
This study was financially supported by the University of Copenhagen (K.D.), the van Andel Research Institut, SU2C (K.G.), and the NovoNordisk Foundation (K.G.) and Independent research fund Denmark (K.G.).

Publisher Copyright:
© 2023 by the authors.

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