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

Agnete Marie Granau, Pilar Aarøe Andersen, Theresa Jakobsen, Konstantina Taouxi, Nawar Dalila, Johanne Bay Mogensen, Lasse Sommer Kristensen, Kirsten Grønbæk*, Konstantinos Dimopoulos*

*Corresponding author af dette arbejde

Abstrakt

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
Udgave nummer2
ISSN2072-6694
DOI
StatusUdgivet - 13 jan. 2023

Fingeraftryk

Dyk ned i forskningsemnerne om 'Concurrent Inhibition of Akt and ERK Using TIC-10 Can Overcome Venetoclax Resistance in Mantle Cell Lymphoma'. Sammen danner de et unikt fingeraftryk.

Citationsformater