AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill &lt;i&gt;FLT3&lt;/i&gt;-ITD acute myeloid leukemia

Post, Sean M.; Ma, Huaxian; Malaney, Prerna; Zhang, Xiaorui; Aitken, Marisa J.L.; Mak, Po Yee; Ruvolo, Vivian; Yasuhiro, Tomoko; Kozaki, Ryohei; Chan, Lauren; Ostermann, Lauren B; Konopleva, Marina; Carter, Bing Z.; DiNardo, Courtney D.; Andreeff, Michael; Khoury, Joseph D.; Ruvolo, Peter P.

doi:10.3324/haematol.2021.278369

Cited by 24 publications

(16 citation statements)

References 36 publications

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“…Apart from Axl, small molecules targeting MerTK and TIM4/3 are in advanced stages of clinical trials. ONO-7475 is a dual Axl–MerTK inhibitor tested in acute leukaemia and myelodysplastic syndromes, either alone or in combination with the chemotherapeutic venetoclax (NCT03176277; Table 1 ), which has been demonstrated to overcome venetoclax resistance in AML models 132 . MRX-2843 is a MerTK/FLT3 inhibitor that aids in treating FLT3 mutations causing AML 133 and is currently undergoing phase I clinical trials (NCT03510104/ NCT04946890; Table 1 ).…”

Section: Efferocytosis In Pathologies and Therapeutic Opportunitiesmentioning

confidence: 99%

Drugging the efferocytosis process: concepts and opportunities

Mehrotra

Ravichandran

2022

Nat Rev Drug Discov

170

109

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The daily removal of billions of apoptotic cells in the human body via the process of efferocytosis is essential for homeostasis. To allow for this continuous efferocytosis, rapid phenotypic changes occur in the phagocytes enabling them to engulf and digest the apoptotic cargo. In addition, efferocytosis is actively anti-inflammatory and promotes resolution. Owing to its ubiquitous nature and the sheer volume of cell turnover, efferocytosis is a point of vulnerability. Aberrations in efferocytosis are associated with numerous inflammatory pathologies, including atherosclerosis, cancer and infections. The recent exciting discoveries defining the molecular machinery involved in efferocytosis have opened many avenues for therapeutic intervention, with several agents now in clinical trials.

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Section: Efferocytosis In Pathologies and Therapeutic Opportunitiesmentioning

confidence: 99%

Drugging the efferocytosis process: concepts and opportunities

Mehrotra

Ravichandran

2022

Nat Rev Drug Discov

170

109

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“…Mainly, monocytic and FLT3-, RAS-, PTPN11- and TP53-mutated AML cells showed resistance to venetoclax caused by higher levels of MCL-1, suggesting that these subgroups of AML cases could be efficiently treated with the combination of venetoclax and a MCL-1 inhibitor [ 97 , 100 ]. Simultaneous inhibition of BCL-2 and MCL-1 synergistically enhances apoptosis in AML cells [ 136 , 137 ]. Even in AML cells that weakly express MCL-1, MCL-1 inhibitors synergized with venetoclax [ 138 ], indicating that the addition of MCL-1 inhibitors to venetoclax treatment might be beneficial for all AML patients.…”

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

confidence: 99%

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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“…81 ONO-7475 even alone exerts an inhibitory effect on FLT3-ITD leukemic cells, related to its capacity to inhibit ERK phosphorylation and expression of the anti-apoptotic protein MCL1. 89 Importantly, the drug combination VEN+ONO-7475 is able to overcome VEN resistance of FLT3-ITD-mutated AML cells. 89 Janssen and coworkers screened in vitro 654 antileukemic compounds in combination with VEN in 31 primary samples of high-risk AMLs and observed that gilteritinib exhibited the highest synergy with VEN in WT FLT3 AMLs.…”

Section: Flt3-mutatedmentioning

confidence: 99%

“…89 Importantly, the drug combination VEN+ONO-7475 is able to overcome VEN resistance of FLT3-ITD-mutated AML cells. 89 Janssen and coworkers screened in vitro 654 antileukemic compounds in combination with VEN in 31 primary samples of high-risk AMLs and observed that gilteritinib exhibited the highest synergy with VEN in WT FLT3 AMLs. 90 Importantly, the VEN+gilteritinib was active in inducing apoptosis of leukemic cell lines and primary AML cells resistant to VEN+AZA.…”

Section: Flt3-mutatedmentioning

confidence: 99%

Section: Outcomes Of Selected Aml Subtypes Following Venetoclax-based...mentioning

confidence: 99%

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The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

Castelli¹,

Testa²

2022

Mediterr J Hematol Infect Dis

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In spite recent progresses, acute myeloid leukemia (AML) remains a disease associated with poor prognosis, particularly in older AML patients unfit to tolerate intensive chemotherapy treatment. The development and introduction in therapy of the drug Venetoclax, a potent BH3 mimetic targeting the antiaopoptotic protein BCL-2, inducing apoptosis of leukemic cells, has shown to be a promising treatment for newly diagnosed, relapsed and refractory AML patients ineligible for induction chemotherapy. Combination treatments using Ventoclax and a hypomethylating agent (azacytidine or decitabine) or low-intensity chemotherapy have shown in newly diagnosed patients variable response rates, with highly responsive patients with NPM1, IDH1-IDH2, TET2 and RUNX1 mutations and with scarcely responsive patients with FLT3, TP53 and ASXL1 mutations, complex karyotypes and secondary AMLs. Patients with refractory/relapsing disease are less responsive to Venetoclax-based regimens. However, in the majority of patients the responses have only a limited duration and development of resistance is frequently observed. Understanding mechanisms of resistance is of crucial importance for the development of new strategies and identification of rational drug combination regimens. In this context, two strategies seem to be promising: (i) triplet therapies based on the combined administration of Venetoclax, a hypomethylating agent (or low-dose chemotherapy) and an agent targeting a specific genetic alteration of leukemic cells (i.e., FLT3 inhibitors in FLT3-mutated AMLs) or an altered signaling pathway; (ii) combination therapies based on the administration of two BH3 mimetics (i.e., BCL-2 +MCL-1 mimetics) and a hypomethylating agent.

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AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill <i>FLT3</i>-ITD acute myeloid leukemia

Cited by 24 publications

References 36 publications

Drugging the efferocytosis process: concepts and opportunities

Drugging the efferocytosis process: concepts and opportunities

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

The Growing Role of the Bh3 Mimetic Drug Venetoclax in the Therapy of Acute Myeloid Leukemia

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