TY - JOUR
T1 - Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies
AU - Griffioen, Mila S.
AU - de Leeuw, David C.
AU - Janssen, Jeroen J. W. M.
AU - Smit, Linda
N1 - Funding Information: This research was funded by the Dutch Cancer Society grant 12805. Publisher Copyright: © 2022 by the authors.
PY - 2022/7/1
Y1 - 2022/7/1
N2 - Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34–90% and 21–33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.
AB - Venetoclax is a BCL-2 inhibitor that effectively improves clinical outcomes in newly diagnosed, relapsed and refractory acute myeloid leukemia (AML) patients, with complete response rates (with and without complete blood count recovery) ranging between 34–90% and 21–33%, respectively. Here, we aim to give an overview of the efficacy of venetoclax-based therapy for AML patients, as compared to standard chemotherapy, and on factors and mechanisms involved in venetoclax sensitivity and resistance in AML (stem) cells, with the aim to obtain a perspective of response biomarkers and combination therapies that could enhance the sensitivity of AML cells to venetoclax. The presence of molecular aberrancies can predict responses to venetoclax, with a higher response in NPM1-, IDH1/2-, TET2- and relapsed or refractory RUNX1-mutated AML. Decreased sensitivity to venetoclax was observed in patients harboring FLT3-ITD, TP53, K/NRAS or PTPN11 mutations. Moreover, resistance to venetoclax was observed in AML with a monocytic phenotype and patients pre-treated with hypomethylating agents. Resistance to venetoclax can arise due to mutations in BCL-2 or pro-apoptotic proteins, an increased dependency on MCL-1, and usage of additional/alternative sources for energy metabolism, such as glycolysis and fatty acid metabolism. Clinical studies are testing combination therapies that may circumvent resistance, including venetoclax combined with FLT3- and MCL-1 inhibitors, to enhance venetoclax-induced cell death. Other treatments that can potentially synergize with venetoclax, including MEK1/2 and mitochondrial complex inhibitors, need to be evaluated in a clinical setting.
KW - AML
KW - biomarkers
KW - resistance
KW - sensitivity
KW - therapeutic combinations
KW - venetoclax (BCL-2 inhibitor)
UR - http://www.scopus.com/inward/record.url?scp=85136397331&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers14143456
DO - https://doi.org/10.3390/cancers14143456
M3 - Review article
C2 - 35884517
SN - 2072-6694
VL - 14
JO - Cancers
JF - Cancers
IS - 14
M1 - 3456
ER -