Dissecting Pirtobrutinib Resistance in Mantle Cell Lymphoma Through Single-Cell Multi-Omics

Area of Science:

• Oncology
• Genomics
• Molecular Biology

Background:

• Pirtobrutinib (PBN), a non-covalent Bruton's tyrosine kinase (BTK) inhibitor, is approved for relapsed/refractory mantle cell lymphoma (MCL).
• Mechanisms underlying resistance to PBN in MCL are not fully understood, hindering the development of effective therapeutic strategies.

Purpose of the Study:

• To investigate the molecular mechanisms driving PBN resistance in mantle cell lymphoma.
• To identify potential therapeutic targets for overcoming PBN resistance.

Main Methods:

• Integrative single-cell multi-omic profiling, including scRNA-seq, scATAC-seq, and scDNA-seq, was performed on longitudinal MCL patient samples.
• Gene regulatory network inference and in silico perturbation analysis were utilized to identify key regulatory elements.

Main Results:

• PBN resistance arises from both genetic alterations (e.g., copy number gains) and non-genetic mechanisms involving transcriptomic and epigenetic remodeling.
• Downregulation of RAD21 and SMC3, components of the cohesin complex, emerged as a potential strategy to re-sensitize MCL cells to PBN.
• A stem-like malignant B cell population with metabolic reprogramming and epithelial-mesenchymal transition features was enriched in resistant samples.

Conclusions:

• PBN resistance in MCL is characterized by heterogeneous, multi-layered mechanisms.
• Chromatin regulators, such as cohesin complex components, represent promising therapeutic targets to overcome PBN resistance in MCL.