A breakthrough discovery reveals why targeting SYK works better than other approaches to overcome treatment resistance in chronic lymphocytic leukemia
Imagine a battlefield where clever cancer cells constantly devise new shields against our most advanced medicines. This isn't science fiction—it's the daily reality in treating chronic lymphocytic leukemia (CLL), the most common form of leukemia in Western countries.
The drug ABT-199 (venetoclax)—a targeted therapy that specifically blocks the BCL-2 protein—initially wipes out leukemia cells in the bloodstream with impressive efficiency. But within protective niches, support cells activate the B-cell receptor (BCR) pathway, prompting leukemia cells to produce more MCL-1, creating a molecular shield that blocks ABT-199's effect 4 7 .
Research now reveals that inhibiting a specific protein called spleen tyrosine kinase (SYK) works remarkably better than other approaches at dismantling this protective shield and restoring ABT-199's cancer-killing power 4 .
The B-cell receptor pathway acts as a master survival switch, involving proteins like SYK, BTK, and PI3Kδ that represent potential drug targets 5 .
Freshly isolated leukemia cells from multiple patients to maintain native biology
Used immobilized anti-IgM antibody to mimic sustained BCR activation 4
Tested SYK inhibitors (R406, GS-9973), BTK inhibitor (Ibrutinib), and PI3Kδ inhibitor (Idelalisib) at clinically relevant concentrations (1μM) 4
| Inhibitor Type | Effect on MCL-1 Synthesis | Effect on MCL-1 Degradation |
|---|---|---|
| SYK inhibitors | Blocks AKT activation | Prevents GSK3 inactivation |
| BTK inhibitor | Blocks AKT activation | No effect on GSK3 |
| PI3Kδ inhibitor | Blocks AKT activation | No effect on GSK3 |
| Treatment | Viable CLL Cells (%) | Significance |
|---|---|---|
| No ABT-199 | 52.2 ± 14.8 | Baseline |
| ABT-199 alone | 28.3 ± 15.1 | P < 0.001 vs no ABT-199 |
| ABT-199 + anti-IgM | 43.0 ± 19.5 | P < 0.001 vs ABT-199 alone |
| ABT-199 + anti-IgM + R406 | 41.7 ± 12.0 | P < 0.001 vs ABT-199 + anti-IgM |
SYK inhibitors uniquely target both sides of the MCL-1 equation—production and destruction 4 . While BTK and PI3Kδ inhibitors block AKT activation (preventing new MCL-1 synthesis), they don't affect GSK3 inactivation. SYK inhibitors target the pathway earlier and more comprehensively, affecting both AKT and GSK3 4 .
SYK inhibition disrupts multiple survival signals, not just BCR signaling. BAFF (B-cell activating factor), a crucial survival cytokine, also depends on SYK to convey protective signals 3 . This positions SYK as a central hub integrating multiple survival signals from the microenvironment.
AKT Activated
MCL-1 Synthesis ↑
GSK3 Inactivated
MCL-1 Degradation ↓
Result: MCL-1 Accumulation
AKT Blocked
MCL-1 Synthesis ↓
GSK3 Active
MCL-1 Degradation ↑
Result: MCL-1 Reduction
The demonstrated superiority of SYK inhibitors in overcoming microenvironment-mediated resistance suggests that combining ABT-199 with SYK inhibitors like entospletinib could benefit several patient groups 4 6 .
Preliminary research shows SYK inhibitor GS-9973 could overcome ABT-199 resistance induced by both BCR stimulation and autologous T-cell activation—another important resistance mechanism 6 .
ABT-199 + SYK inhibitor to directly counter MCL-1 resistance
ABT-199 with BCR inhibitors and anti-CD20 antibodies
SYK inhibition clears protective niches before ABT-199 administration
The discovery that SYK inhibition more effectively overcomes MCL-1-mediated ABT-199 resistance than BTK or PI3Kδ inhibition represents more than just an incremental advance—it provides crucial insight into the hierarchical organization of survival pathways in CLL cells. By identifying SYK as a superior target for disrupting the protective microenvironment, this research opens new avenues for designing more effective, durable combination therapies.
As clinical trials begin to translate these laboratory findings into patient treatments, we move closer to a future where CLL can be consistently transformed from a chronic, relapsing condition into a reliably manageable disease.