biorxiv.org· Wang, Q., Xu, S., Cai, J., Peng, Q., Cao, S., Zhang, Y., Lu, P., Guo, X., Liu, L., Fu, W., Shao, S., Zhu, J., Qing, B., Li, H., Liu, K., Zhu, K., Yang, H., Yang, X., Zhu, G. ·2026-10-16 08:00· 15 hours agoPickScore59

Venetoclax Resistance Creates Canonical Pyroptosis Vulnerability in AML

In brief

Venetoclax-resistant AML cells, which often adopt monocytic differentiation, retain the canonical pyroptosis machinery of normal monocytes. Across 15 bulk and 4 single-cell cohorts, this pyroptosis program tracked with venetoclax resistance and inferior survival after venetoclax-based therapy; in 24 cell lines and 142 patient specimens, DPP8/9 inhibition by Val-boroPro or NLRP3 activation preferentially killed monocytic AML via GSDMD-mediated pyroptosis. In venetoclax-resistant xenografts, Val-boroPro plus venetoclax reduced leukemia burden and prolonged survival beyond either monotherapy.

Why it matters

It identifies pyroptosis as a druggable vulnerability created by venetoclax resistance in monocytic AML.

Source: biorxiv.org · biorxiv.org

#Preprint #Oncology #Small molecules & degraders