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

SIMPLE SUMMARY: Targeting BCL-2 through venetoclax is an effective therapy for a series of hematological cancers, such as mantle cell lymphoma (MCL), but resistance to venetoclax is an increasing challenge that needs to be overcome. In order to elucidate the resistance mechanisms to venetoclax in MCL at a molecular level, we used an in vitro model of acquired resistance and performed genetic, epigenetic and transcriptomic analyses. We found that venetoclax-resistant (VR) cells acquired a TP53 mutation and consequently exhibited a reduced apoptotic response. In addition, transcriptomic analysis showed an upregulation of the PI3K/Akt pathway in the VR cells, and an extensive drug screen revealed that Akt and ERK inhibition with TIC10 could induce apoptosis in VR cells with both acquired and intrinsic venetoclax resistance. Thus, TIC-10 might be a possible treatment option for VR patients that requires further investigation. ABSTRACT: 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.