Use of Receptor and Non-receptor Tyrosine Kinase Inhibitors Is Associated with Lower Risk of Developing Parkinson Disease
Giovanni Malaty1, Susan Nielsen2, Osvaldo Laurido-Soto2, Brad Racette1
1Barrow Neurological Institute, 2Washington University in St. Louis
Objective:
To test the association between the use of receptor tyrosine kinase inhibitors (rTKI)/non-receptor tyrosine kinase inhibitors (nrTKI) and Parkinson disease (PD) risk.
Background:
Currently, no disease-modifying therapies exist for PD. Receptor and non-receptor tyrosine kinases such as Abelson tyrosine kinase (ABL) are implicated in PD pathogenesis via their induction of neuroinflammation, α-synuclein phosphorylation/aggregation, and mitochondrial dysfunction resulting in neuronal toxicity and death. Although a randomized controlled trial of the ABL inhibitor nilotinib failed to demonstrate evidence of disease modification, other rTK/nrTK inhibitors may still be promising as neuroprotective therapies.
Design/Methods:
Using U.S. Medicare data, we conducted a population-based, case-control study of 200,437 incident PD patients and 941,727 comparable, population-based controls diagnosed/selected in 2016-2018. We tested the association between Part D prescription fills in the prior 2-5 years for seven rTKIs (Erlotinib, Imatinib, Nilotinib, Nintedanib, Pazopanib, Sorafenib, Sunitinib) and four nrTKIs (Dasatinib, Ibrutinib, Ruxolitinib, and Tofacitinib) and PD risk. We used logistic regression to estimate relative risks (RR) and 95% confidence intervals (CI), and to adjust for demographics, smoking, and healthcare utilization.
Results:
All 11 TK inhibitors were inversely-associated with PD. Beneficiaries taking tyrosine kinase inhibitors targeting ERBb (Erlotinib, RR 0.51, CI 0.35-0.74), TEC (Ibrutinib, RR 0.60, CI 0.49-0.74), or PDGF, VEGF, FGFR, and/or SRC, i.e. Sorafenib (RR 0.48, CI 0.27-0.84), Imatinib (RR 0.59, CI 0.46-0.75), Pazopanib (RR 0.58, CI 0.39-0.88), Nintedanib (RR 0.67, CI 0.50-0.90), Sunitinib (RR 0.64, CI 0.41-1.00), and Dasatinib (RR 0.54, CI 0.35-0.83) tended to have the most marked inverse associations. The nrTKIs inhibiting JAK, i.e., Ruxolitinib (RR 0.81, CI 0.60-1.10) and Tofacitinib (RR 0.88, CI 0.68-1.14), exhibited more modest inverse associations, as did the ABL/PDGF inhibitor Nilotinib (RR 0.71, CI 0.47-1.09).
Conclusions:
rTKIs and nrTKIs might reduce risk of developing PD and there may be some differential impact of this class of medications depending on specific inhibition pathways and indication.