Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia

Zhang, Qi; Riley-Gillis, Bridget; Han, Lei; Jia, Yanan; Lodi, Alessia; Zhang, Haijiao; Ganesan, Saravanan; Pan, Rongqing; Konoplev, Sergej; Sweeney, Shannon R.; Ryan, Jeremy; Jitkova, Yulia; Dunner, Kenneth; Grosskurth, Shaun; Vijay, Priyanka; Ghosh, Sujana; Lu, Charles; Ma, Wencai; Kurtz, Stephen E.; Ruvolo, Vivian; Ma, Helen; Weng, Connie C.; Ramage, Cassandra L; Baran, Natalia; Shi, Ce; Cai, Tianyu; Davis, R. Eric; Battula, Venkata Lokesh; Mi, Yingchang; Wang, Jing; DiNardo, Courtney D.; Andreeff, Michael; Tyner, Jeffery W.; Schimmer, Aaron D.; Letaï, Anthony; Padua, Rose Ann; Bueso‐Ramos, Carlos E.; Tiziani, Stefano; Leverson, Joel D.; Popovic, Relja; Konopleva, Marina

doi:10.1038/s41392-021-00870-3

Cited by 86 publications

(63 citation statements)

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“…Studies have shown that the total level of mitogen-activated protein kinase (MAPK) in TP53 mutant cells is increased. The MAPK signalling pathway is involved in the regulation of cell proliferation and apoptosis and can increase the expression of MCL-1 protein, thereby increasing the competitive binding of MCL-1 and BCL-2 to venetoclax and thus affecting venetoclax-mediated cell apoptosis [ 45 , 58 – 61 ]. Further studies have shown that the expression level of BCL-XL was increased and the levels of PMAIP1 (NOXA), PUMA and BAK were decreased in a TP53 knockout cell line with reduced sensitivity to venetoclax, which caused inhibition of apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

2022

Exp Hematol Oncol

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Venetoclax is a new type of BH3 mimetic compound that can target the binding site in the BCL-2 protein and induce apoptosis in cancer cells by stimulating the mitochondrial apoptotic pathway. Venetoclax is especially used to treat haematological malignancies. However, with the recent expansion in the applications of venetoclax, some cases of venetoclax resistance have appeared, posing a major problem in clinical treatment. In this article, we explored several common mechanisms of venetoclax resistance. Increased expression of the antiapoptotic proteins MCL-1 and BCL-XL plays a key role in conferring cellular resistance to venetoclax. These proteins can bind to the released BIM in the context of venetoclax binding to BCL-2 and thus continue to inhibit mitochondrial apoptosis. Structural mutations in BCL-2 family proteins caused by genetic instability lead to decreased affinity for venetoclax and inhibit the intrinsic apoptosis pathway. Mutation or deletion of the BAX gene renders the BAX protein unable to anchor to the outer mitochondrial membrane to form pores. In addition to changes in BCL-2 family genes, mutations in other oncogenes can also confer resistance to apoptosis induced by venetoclax. TP53 mutations and the expansion of FLT3-ITD promote the expression of antiapoptotic proteins MCL-1 and BCL-XL through multiple signalling pathways, and interfere with venetoclax-mediated apoptosis processes depending on their affinity for BH3-only proteins. Finally, the level of mitochondrial oxidative phosphorylation in venetoclax-resistant leukaemia stem cells is highly abnormal. Not only the metabolic pathways but also the levels of important metabolic components are changed, and all of these alterations antagonize the venetoclax-mediated inhibition of energy metabolism and promote the survival and proliferation of leukaemia stem cells. In addition, venetoclax can change mitochondrial morphology independent of the BCL-2 protein family, leading to mitochondrial dysfunction. However, mitochondria resistant to venetoclax antagonize this effect, forming tighter mitochondrial cristae, which provide more energy for cell survival.

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Section: Introductionmentioning

confidence: 99%

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

2022

Exp Hematol Oncol

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“…In AML patients that progress or relapse after treatment with venetoclax and azacitidine, 27% of the patients had a N/KRAS mutation, and 22% a PTPN11 mutation [ 32 , 95 ], suggesting that these mutations are more frequently present in refractory or relapsed disease. The reduced sensitivity to venetoclax in RAS- and PTPN11-mutated AML patients can be explained by the activation of the RAS/MAPK signaling pathway [ 96 ], allowing the AML cells in RAS- and PTPN11-mutated cases to use multiple sources of energy for cell survival, including fatty acid and amino acid metabolism, glycolysis and upregulation of OXPHOS [ 97 , 98 ]. Moreover, AML with a PTPN11 mutation often has a more monocytic cell type [ 99 ], which generally has increased dependency on MCL-1 instead of BCL-2 [ 100 ], thereby decreasing the efficacy of venetoclax.…”

Section: Aml Patients With Mutations In Flt3 Tp53 and Ras Showed Redu...mentioning

confidence: 99%

“…In some AML patients, leukemic cell survival depends on other functional anti-apoptotic proteins than BCL-2, for example MCL-1 ( Figure 1 B) [ 119 ]. These patients may have primary resistance to venetoclax-based therapies due to the upregulation of MCL-1, which is stabilized through epigenetic modifications caused by the activation of the RAS/MAPK signaling pathway [ 96 , 111 ]. As previously mentioned, AML cells with a more monocytic AML cell type or the FLT3, RAS, PTPN11 or TP53 mutations have increased dependency on MCL-1 instead of on BCL-2 [ 90 , 100 , 101 , 110 , 120 ].…”

Section: Mechanisms Determining Sensitivity Of Aml To Venetoclaxmentioning

confidence: 99%

“…The increased dependency on MCL-1 is caused by activation of the MAPK signaling pathway, which stabilizes the MCL-1 protein and prevents its degradation [ 96 , 111 ]. Inhibition of the MAPK signaling pathway with MEK1/2 inhibitors synergizes with venetoclax to prevent survival in AML cells [ 102 ].…”

Section: Prediction Of Active Venetoclax-based Combination Therapies ...mentioning

confidence: 99%

“…Simultaneous inhibition downregulated MCL-1 levels and disrupted the binding of BIM to both BCL-2 and MCL-1 and released BIM to initiate apoptosis [ 102 ]. Venetoclax combined with MEK1/2 inhibitors might therefore improve response rates in RAS-, PTPN11- and FLT3-ITD-mutated AML patients since these mutations activate the MAPK signaling pathway [ 83 , 96 ].…”

Section: Prediction Of Active Venetoclax-based Combination Therapies ...mentioning

confidence: 99%

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Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies

Griffioen

Leeuw

Janssen

et al. 2022

Cancers

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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.

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Co‐Targeting c‐Myc and Bcl‐2 by Oral Small Molecule Combination of WBC100 and Venetoclax Effectively Controls Acute Myeloid Leukemia in Preclinical Models

Wang

Zheng

et al. 2023

Advanced Therapeutics

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Uncontrolled proliferation and apoptosis evasion are two hallmarks of acute myeloid leukemia (AML), but the molecular mechanisms remain poorly understood. In this study, it is demonstrated that the double over‐expresser of oncoprotein c‐Myc and anti‐apoptotic protein Bcl‐2 is a critical “genetic overdrive” of proliferation and apoptosis evasion in AML and is associated with poor genetic alterations. Double‐knockdown of c‐Myc/ Bcl‐2 synergistically kills AML cells in vitro and in vivo. Moreover, a novel oral small molecule combination co‐targeting c‐Myc and Bcl‐2 with WBC100 and Venetoclax (VEN) at low doses are developed. Importantly, the study shows that this combination results in deep and durable remissions of AML, and its efficacy is superior to the frontline combination of Venetoclax and hypomethylation azacitidine (AZA) in AML mouse models and PDX models from relapsed or refractory AML patients. Mechanically, Bcl‐2 knockdown induces mitochondrial outer membrane permeabilization and c‐Myc‐knockdown impairs mitochondria biogenesis. Co‐targeting c‐Myc/Bcl‐2 reciprocally abrogates over‐proliferation and apoptosis resistance via forming a double hit to mitochondrial biogenesis and apoptosis machinery. The findings for the first time demonstrate that co‐targeting c‐Myc/Bcl‐2 by the novel oral small molecule combination of WBC100/Venetoclax is a promising and convenient therapy for AML and support its clinical trial.

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Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia

Cited by 86 publications

References 50 publications

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

Targeting Acute Myeloid Leukemia with Venetoclax; Biomarkers for Sensitivity and Rationale for Venetoclax-Based Combination Therapies

Co‐Targeting c‐Myc and Bcl‐2 by Oral Small Molecule Combination of WBC100 and Venetoclax Effectively Controls Acute Myeloid Leukemia in Preclinical Models

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