Venetoclax Overcomes Sorafenib Resistance in Acute Myeloid Leukemia by Targeting BCL2

SIMPLE SUMMARY: Drug resistance is the main cause of sorafenib treatment failure in clinical acute myeloid leukemia (AML) patients, but the mechanism is currently not fully clear. In this study, we analyzed the genetic characteristics of sorafenib-resistant AML cell subclusters using single-cell and bulk transcription data and found that sorafenib-resistant AML cells can promote BCL2 transcription by activating STAT3. The BCL2 inhibitor venetoclax can enhance the chemotherapy sensitivity of AML cells to sorafenib. ABSTRACT: 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.