Aberrant expression of MERTK activates BCR via CD79a in CLL cells: alternative therapeutic strategy for relapsed/refractory CLL.

Although therapies targeting BTK of BCR-signal are changing the landscape of CLL management, these agents are not curative and resistance can develop. Thus, we searched for other druggable target(s) regulating leukemic B-cell survival for developing alternative therapies. We detected MERTK, a member of the TAM (Tyro3, AXL, MERTK) family receptor tyrosine kinases (RTKs), is aberrantly expressed and constitutively active in CLL cells from ~65% CLL patients (n = 100). Ligation of Gas6, a common ligand for TAM-RTKs, preferentially activated MERTK resulting in activation of NF-κB/AKT/Erk1/2 and BTK in CLL cells. Partial depletion of MERTK in CLL cells reduced P-Erk1/2, P-NF-κB, P-AKT, and P-BTK levels, suggesting that MERTK may crosstalk with BCR-signal. Indeed, MERTK activated BTK by forming a signalosome with CD79a/LYN in CLL cells. Interestingly, stimulation of BCR-signals in CLL cells activated MERTK via CD79a, suggesting that MERTK/BCR-signals are functionally connected. Importantly, targeting MERTK using a high-affinity, pharmacologic inhibitor UNC-2025 induced apoptosis in CLL cells and reduced leukemic burden in vivo. More significantly, ibrutinib-resistant CLL cells expressed high-levels of MERTK and that, UNC-2025 synergistically induced apoptosis when combined with venetoclax. Thus, high MERTK-levels in CLL cells may be associated with ibrutinib-resistance underscoring the potential use of UNC-2025/venetoclax combination in treating relapsed/refractory patients.