| アブストラクト | BACKGROUND: Cutaneous T cell lymphoma (CTCL) is an incurable cancer characterized by elevated p38beta and p38gamma and downregulated tumor-suppressive p38alpha. OBJECTIVES: We aimed to identify selective p38beta 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 p38beta 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 p38beta inhibitor (~25-fold over p38alpha). Its inhibition of p38beta led to compensatory activation of p38gamma, driving Epithelial-to-Mesenchymal Transition (EMT) and potential toxicities. Combining Nilotinib with p38gamma 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 p38beta but activates p38gamma, potentially reducing therapeutic selectivity. Combining it with p38gamma inhibitors may enhance efficacy and reduce toxicity across hematologic malignancies. |
|---|
| 投稿者 | Zhang, Xu Hannah; Hsiang, Jack; Nam, Sangkil; Li, Hongzhi; Yuan, Yate-Ching; Wu, Xiwei; Hmwe, Susan; Moore, Roger; Rosen, Steven T |
|---|
| 組織名 | Department of Hematology & Hematopoietic Cell Transplantation, Beckman Research;Institute, City of Hope, Duarte, CA, USA.;High Throughput Screening Core Shared research facility, Beckman Research;Bioinformatics Core Shared Research Facilities, Beckman Research Institute, City;of Hope, Duarte, CA, USA.;Integrative Genomics Core Shared Research Facilities, Beckman Research Institute,;City of Hope, Duarte, CA, USA.;Department of System Clinical Trial Technology & Data Solutions Department,;Beckman Research Institute, City of Hope, Duarte, CA, USA.;Integrated Mass Spectrometry Core Facility, Beckman Research Institute, City of;Hope, Duarte, CA, USA. |
|---|
