Venetoclax Overcomes Sorafenib Resistance in Acute Myeloid Leukemia by Targeting BCL2
- Biology (Basel). 2023 Oct 16;12(10):1337. doi: 10.3390/biology12101337.
- 1. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510091, China.
- 2. Department of Hematology, The Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China.
- 3. Key Laboratory of Stem Cells and Tissue Engineering, Zhongshan School of Medicine, Sun Yat-sen University, Ministry of Education, Guangzhou 510080, China.
- 4. Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510080, China.
- 5. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510080, China.
Sorafenib, a kinase inhibitor, has shown promising therapeutic efficacy in a subset of patients with acute myeloid leukemia (AML). However, despite its clinical effectiveness, sorafenib resistance is frequently observed in clinical settings, and the mechanisms underlying this resistance as well as effective strategies to overcome it remain unclear. We examined both single-cell and bulk transcription data in sorafenib-resistant and control AML patients and integrated a sorafenib resistance gene signature to predict the sensitivity of AML cells and the clinical outcomes of AML patients undergoing sorafenib therapy. In addition, our drug sensitivity analysis of scRNA-seq data using deconvolution methods showed that venetoclax was effective in targeting sorafenib-resistant AML cells. Mechanistically, sorafenib was found to activate the JAK-STAT3 pathway and upregulate BCL2 expression in sorafenib-resistant AML cells. This upregulation of BCL2 expression rendered the cells vulnerable to the BCL2 inhibitor venetoclax. In conclusion, we developed a platform to predict sorafenib resistance and clinical outcomes in AML patients after therapy. Our findings suggest that the combination of sorafenib and venetoclax could be an effective therapeutic strategy for AML treatment.