Author:
Riabov Vladimir,Xu Qingyu,Schmitt Nanni,Streuer Alexander,Ge Guo,Bolanos Lyndsey,Wunderlich Mark,Jann Johann-Christoph,Wein Alina,Altrock Eva,Demmerle Marie,Mukherjee Sanjay,Ali Abdullah Mahmood,Rapp Felicitas,Nowak Verena,Weimer Nadine,Obländer Julia,Palme Iris,Göl Melda,Jawhar Ahmed,Darwich Ali,Wuchter Patrick,Weiss Christel,Raza Azra,Foulks Jason M.,Starczynowski Daniel T,Yang Feng-Chun,Metzgeroth Georgia,Steiner Laurenz,Jawhar Mohamad,Hofmann Wolf-Karsten,Nowak Daniel
Abstract
Inhibitors of anti-apoptotic BCL-2 family proteins in combination with chemotherapy and hypomethylating agents (HMAs) are promising therapeutic approaches in acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS). Alvocidib, a cyclin-dependent kinase 9 (CDK9) inhibitor and indirect transcriptional repressor of the anti-apoptotic factor MCL-1, has previously shown clinical activity in AML. Availability of biomarkers for response to the alvocidib + 5- AZA could also extend the rationale of this treatment concept to high-risk MDS. In this study, we performed a comprehensive in vitro assessment of alvocidib and 5-AZA effects in n=45 high-risk MDS patients. Our data revealed additive cytotoxic effects of the combination treatment. Mutational profiling of MDS samples identified ASXL1 mutations as predictors of response. Further, increased response rates were associated with higher gene-expression of the pro-apoptotic factor NOXA in ASXL1 mutated samples. The higher sensitivity of ASXL1 mutant cells to the combination treatment was confirmed in vivo in ASXL1Y588X transgenic mice. Overall, our study demonstrated augmented activity for the alvocidib + 5-AZA combination in higher-risk MDS and identified ASXL1 mutations as a biomarker of response for potential stratification studies.
Publisher
Ferrata Storti Foundation (Haematologica)