Targeting MERTK in CLL: A Promising Strategy for Overcoming Ibrutinib Resistance

Highlight

• MERTK is aberrantly expressed and constitutively active in approximately 65% of CLL patient cells.
• MERTK activation engages NF-κB, AKT, Erk1/2, and crucially activates BTK via direct interaction with CD79a and LYN.
• Bidirectional crosstalk exists between MERTK and B-cell receptor (BCR) signaling pathways in CLL cells.
• Pharmacologic inhibition of MERTK with UNC-2025 induces apoptosis in CLL cells, reduces leukemic burden in vivo, and enhances efficacy when combined with venetoclax, particularly against ibrutinib-resistant CLL.

Study Background