Abstract
Background: Cutaneous T cell lymphoma (CTCL) is an incurable cancer characterized by elevated p38β and p38γ and downregulated tumor-suppressive p38α.
Objectives: We aimed to identify selective p38β inhibitors and investigate their mechanisms and therapeutic implications in hematologic malignancies.
Methods: A high-throughput screen of Food and Drug Administration (FDA)-approved compounds was conducted to identify p38β inhibitors. In vitro kinase assays, Western blots, scRNA-seq, synergy tests, and mass spectrometry were used. Clinical trial and public datasets were analyzed.
Results: Nilotinib was identified as a selective p38β inhibitor (~25-fold over p38α). Its inhibition of p38β led to compensatory activation of p38γ, driving Epithelial-to-Mesenchymal Transition (EMT) and potential toxicities. Combining Nilotinib with p38γ inhibitors (e.g., CSH71 or Paclitaxel) produced synergistic anti-tumor effects in CTCL and leukemia cells. Clinical and FDA Adverse Event Reporting System (FAERS) data revealed higher toxicity rates for Nilotinib in Ph+ CML and off-target effects in non-CML cancers.
Conclusion: Nilotinib selectively inhibits p38β but activates p38γ, potentially reducing therapeutic selectivity. Combining it with p38γ inhibitors may enhance efficacy and reduce toxicity across hematologic malignancies.
Keywords
Chronic myeloid leukemia, Clinical trials, Cutaneous T cell lymphoma, Nilotinib, Paclitaxel