Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia

Brinton, Lindsey T.; Zhang, Pu; Williams, Katie; Canfield, Daniel; Orwick, Shelley; Sher, Steven; Wasmuth, Ronni; Beaver, Larry; Cempre, Casey B.; Skinner, Jordan; Cannon, Matthew; Govande, Mukul; Harrington, Bonnie K.; Lehman, Amy; Byrd, John C.; Lapalombella, Rosa; Blachly, James S.

doi:10.1186/s13045-020-00973-4

Cited by 48 publications

(39 citation statements)

References 20 publications

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“…However, clinical experiences with FLT3 inhibitors monotherapy has shown a short duration of response and a high rate of relapse [ 17 , 20 ], suggesting that combination strategies may be needed to improve clinical outcomes. Previous studies have suggested a synergistic effect of BCL-2 inhibition and FLT3 inhibition in preclinical models of FLT3-ITD mutant AML [24] . Therefore, we next sought to investigate the combination of HQP1351 and BCL-2 inhibitor APG-2575 in FLT3-ITD mutant AML models.…”

Section: Resultsmentioning

confidence: 94%

“…Overexpression of BCL-2 is associated with therapeutic resistance and is a biomarker for worse responses to chemotherapy in patients with AML [21] , [22] , [23] . In an unbiased, large-scale clustered regularly interspaced short palindromic repeats (CRISPR) screening, knockout of BCL-2 enhanced the anti-leukemic effects of FLT3 inhibitors in AML [24] . Venetoclax, a potent and selective BCL-2 inhibitor, has been developed and approved by the FDA in combination with low-dose cytarabine (LDAC) or hypomethylating agents for treatment of elderly patients with AML or those who are ineligible for intensive chemotherapy [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

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FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

Fang¹,

Zhu²,

Tang³

et al. 2022

Translational Oncology

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Introduction FLT3-ITD mutations occur in approximately 25% of patients with acute myeloid leukemia (AML) and are associated with poor prognosis. Despite initial efficacy, short duration of response and high relapse rates limit clinical use of selective FLT3 inhibitors. Combination approaches with other targeted therapies may achieve better clinical outcomes. Materials and methods Anti-leukemic activity of multikinase inhibitor olverembatinib (HQP1351), alone or in combination with BCL-2 inhibitor lisaftoclax (APG-2575), was evaluated in FLT3-ITD mutant AML cell lines in vitro and in vivo . A patient-derived FLT3-ITD mutant AML xenograft model was also used to assess the anti-leukemic activity of this combination. Results HQP1351 potently induced apoptosis and inhibited FLT3 signaling in FLT3-ITD mutant AML cell lines MV-4-11 and MOLM-13. HQP1351 monotherapy also significantly suppressed growth of FLT3-ITD mutant AML xenograft tumors and prolonged survival of tumor-bearing mice. HQP1351 and APG-2575 synergistically induced apoptosis in FLT3-ITD mutant AML cells and suppressed growth of MV-4–11 xenograft tumors. Combination therapy improved survival of tumor bearing-mice in a systemic MOLM-13 model and showed synergistic anti-leukemic effects in a patient-derived FLT3-ITD mutant AML xenograft model. Mechanistically, HQP1351 downregulated expression of myeloid-cell leukemia 1 (MCL-1) by suppressing FLT3-STAT5 (signal transducer and activator of transcription 5) signaling and thus enhanced APG-2575-induced apoptosis in FLT3-ITD mutant AML cells. Conclusions FLT3 inhibition by HQP1351 downregulates MCL-1 and synergizes with BCL-2 inhibitor APG-2575 to potentiate cellular apoptosis in FLT3-ITD mutant AML. Our findings provide a scientific rationale for further clinical investigation of HQP1351 combined with APG-2575 in patients with FLT3-ITD mutant AML.

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Section: Resultsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

Fang¹,

Zhu²,

Tang³

et al. 2022

Translational Oncology

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“…sustainable CR. One way to improve these results is the simultaneous use of combination of targeted therapy, as illustrated by the synergistic effect of BCL-2 and FLT-3 co-inhibition [ 39 ]. The mechanisms evoked for escape from targeted therapies are obviously multiple, and linked both to the state of the tumor at the beginning of treatment but also to its evolution under treatment, under the possible pressure of targeted therapy +/− conventional chemotherapy +/− adoptive immunotherapy +/− immunity developed by the patient.…”

Section: The Results Obtained By Targeted Therapiesmentioning

confidence: 99%

The contribution of single-cell analysis of acute leukemia in the therapeutic strategy

et al. 2021

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After decades during which the treatment of acute myeloblastic leukemia was limited to variations around a skeleton of cytarabine/anthracycline, targeted therapies appeared. These therapies, first based on monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the tumor heterogeneity inherent to leukemia and the clonal drift of which this type of tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of leukemia, either spontaneous or under therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/immunotherapy (“pan-resistant clones”), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-chemotherapy of remaining leukemic cells.

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“…The combination between a FLT3 inhibitor and venetoclax in vitro and in vivo has validated therapeutic effect against various models of FLT3-ITD-driven AML (ref. 37 ). The same technology was used to obtain exportin 1 (XPO1) knockout.…”

Section: Therapeutic Advancesmentioning

confidence: 99%

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia

Mihăilă¹,

Topircean²

2021

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Knowledge on acute myeloid leukemia pathogenesis and treatment has progressed recently, but not enough to provide ideal management. Improving the prognosis of acute myeloid leukemia patients depends on advances in molecular biology for the detection of new therapeutic targets and the production of effective drugs. The CRISPR/Cas9 technology allows gene insertions and deletions and it is the first step in investigating the function of their encoded proteins. Thus, new experimental models have been developed and progress has been made in understanding protein metabolism, antitumor activity, leukemic cell maintenance, differentiation, growth, apoptosis, and self-renewal, the combined pathogenetic mechanisms involved in leukemogenesis. The CRISPR/Cas9 system is used to understand drug resistance and find solutions to overcome it. The therapeutic progress achieved using the CRISPR/Cas9 system is remarkable. FST gene removal inhibited acute myeloid leukemia cell growth. Lysine acetyltransferase gene deletion contributed to decreased proliferation rate, increased apoptosis, and favored differentiation of acute myelid leukemia cells carrying MLL-X gene fusions. The removal of CD38 gene from NK cells decreased NK fratricidal cells contributing to increased efficacy of new CD38 CAR-NK cells to target leukemic blasts. BCL2 knockout has synergistic effects with FLT3 inhibitors. Exportin 1 knockout is synergistic with midostaurin treatment in acute myeloid leukemia with FLT3-ITD mutation. Using the results of CRISPR/Cas9 libraries and technology application will allow us to get closer to achieving the goal of curing acute myeloid leukemia in the coming decades.

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Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia

Cited by 48 publications

References 20 publications

FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

The contribution of single-cell analysis of acute leukemia in the therapeutic strategy

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia

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