Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a poor prognosis.
• Understanding the molecular pathways driving MCL is crucial for developing effective therapies.

Purpose of the Study:

• To identify mechanisms of resistance to B cell receptor (BCR) signaling inhibitors in MCL.
• To uncover novel therapeutic targets for MCL, particularly for treatment-refractory cases.

Main Methods:

• Pharmacological profiling of over 100 hematological cell lines.
• Transcriptome sequencing and mutation analysis of MCL cell lines and patient samples.
• In vitro and in vivo functional assays to assess drug sensitivity and pathway dependence.

Main Results:

• MCL cell lines showed differential sensitivity to BCR inhibitors (ibrutinib, sotrastaurin) linked to distinct NF-κB pathway activation (classical vs. alternative).
• Ibrutinib-insensitive MCL harbored genetic lesions in the alternative NF-κB pathway (TRAF2, BIRC3 mutations in 15% of patients).
• Alternative pathway lesions conferred dependence on protein kinase NIK (MAP3K14), identifying it as a therapeutic target.

Conclusions:

• MCL exhibits mutually exclusive activation of BCR-NF-κB and NIK-NF-κB pathways.
• NIK represents a promising therapeutic target for MCL refractory to BCR pathway inhibitors.
• Findings offer strategies for patient stratification for NF-κB pathway-targeted therapies.