Repurposing Nilotinib as a Selective P38β Inhibitor in Hematopoietic Malignancies: Clinical Evidence and Mechanistic Insights

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.