Researchers at the University of Sussex and collaborating institutions have discovered that chronic lymphocytic leukemia cells can evade treatment by switching survival pathways. When Bruton's tyrosine kinase inhibitors block the standard B-cell receptor signaling pathway, leukemia cells can switch to Toll-like receptor 9 signaling to remain viable. Using patient-validated computer models, the team demonstrated how this mechanism explains treatment resistance in the 20% to 30% of relapsed patients without detectable genetic mutations.
Mechanism and implications of TLR9 pathway switching
- ▪Identifying Toll-like receptor 9 pathway switching in chronic lymphocytic leukemia cells can assist clinicians in selecting effective combination drug regimens earlier while avoiding ineffective treatments and unnecessary side effects.
- ▪A study led by researchers including Simon Mitchell, Andrea Pepper, Chris Pepper, and Emma Kennedy demonstrated that chronic lymphocytic leukemia cells evade treatment by switching from blocked B-cell receptor pathways to Toll-like receptor 9 signaling.
Computer modeling of B-Cell receptor signaling
- ▪The study published in Blood represents the first detailed computer model of B-cell receptor signaling in chronic lymphocytic leukemia to be directly tested and validated using patient-derived cells.
- ▪Professor Simon Mitchell of the University of Sussex developed mathematical computer models to predict how chronic lymphocytic leukemia cells from individual patients respond to survival signals.
How Bruton's tyrosine kinase inhibitors work
- ▪Disrupting the B-cell receptor pathway forces chronic lymphocytic leukemia cells out of protective lymph nodes and into the bloodstream where targeted therapies can eliminate them.
- ▪Bruton's tyrosine kinase inhibitor drugs disrupt the B-cell receptor communication pathway that chronic lymphocytic leukemia cells rely on for survival.
Challenges in treating chronic lymphocytic leukemia
- ▪Chronic lymphocytic leukemia is the most common adult leukemia and remains an incurable condition despite advances in Bruton's tyrosine kinase inhibitor therapies.
- ▪In chronic lymphocytic leukemia patients treated with chemoimmunotherapy, TP53 alterations represent a primary genetic consideration associated with treatment resistance and chemo-refractory disease.
- ▪For 20% to 30% of chronic lymphocytic leukemia patients who relapse after treatment, drug resistance occurs without any detectable genetic mutations.
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