In Vivo CLL Proliferation Is Targeted by BTK Inhibition: ERK Activity Predicts Patient Nodal Response
Y Lynn Wang, Shuhua Cheng, Jiao Ma, Ailin Guo, Pin Lu, Lauren Tyrell, Joseph J Buggy, John P Leonard, Richard R Furman. Weill Cornell Medical College, New York, NY; Pharmacyclics Inc., Sunnyvale, CA
Background: B-cell receptor signaling plays an essential role in the pathogenesis of chronic lymphocytic leukemia (CLL). BTK, a cytoplasmic tyrosine kinase, is one of the key components of the early BCR signaling pathway. A novel BTK inhibitor, PCI-32765, has demonstrated remarkable clinical activity against CLL in a multi-center phase Ib clinical trial. A better understanding of the molecular mechanisms of drug action would shed light on CLL pathophysiology and provide more opportunities for the development of new therapies.
Design: To this end, we have undertaken an unconventional in vivo approach by taking advantage of an ongoing phase 1b clinical trial of PCI-32765 in CLL patients. We prospectively collected serial samples from trial patients before and at multiple time points after the initiation of therapy and analyzed them for cellular and molecular signaling events. The longitudinal changes in these parameters were correlated with clinical responses in patients.
Results: We found that blockage of cell proliferation, as opposed to apoptosis, is the primary effect of PCI-32765 against leukemic CLL cells in vivo. BrdU incorporation of CLL cells was directly inhibited by PCI-32765 in an in vitro model of CLL proliferation. Further, several markers were identified that may serve as therapeutic response predictors, including cellular proliferative markers Ki67 and signal transducer ERK. Downregulation of both Ki67 and ERK activity occurred prior to clinical responses seen in the patient cohort. Moreover, the dynamic changes over treatment course quantitatively correlated with the degree of patient's nodal mass reduction.
Conclusions: These results have several implications: 1) They highlight the key role of cell proliferation in CLL. We demonstrated for the first time that blocking cell proliferation via inhibition of BCR signaling is linked to clinical responses in patients; 2) ERK activity contributes to the in vivo CLL proliferation. ERK signaling pathway, therefore, represents a potential therapeutic target for future interventions; and 3) Ki67 and ERK may be used as response predictors for future trials of BTK inhibitors.
Monday, March 19, 2012 1:00 PM
Poster Session II # 203, Monday Afternoon