LAM-003, a new drug for treatment of tyrosine kinase inhibitor–resistant FLT3-ITD–positive AML

Beeharry, Neil; Landrette, Sean F.; Gayle, Sophia; Hernandez, Marylens; Grotzke, Jeff E.; Young, Peter R.; Beckett, Paul; Zhang, Xuan; Carter, Bing Z.; Andreeff, Michael; Halene, Stephanie; Xu, Tian; Rothberg, Jonathan M.; Lichenstein, Henri S.

doi:10.1182/bloodadvances.2019001068

Cited by 14 publications

(10 citation statements)

References 69 publications

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“…TP-0903 overcomes resistance due to bone marrow microenvironment-mediated factors. Recent preclinical studies indicate that FLT3-ITD-mutated AML cells are rescued from FLT3 inhibition due to bone marrow microenvironment-mediated factors including stromal cells, involving direct cell-cell contact and soluble factors, as well as hematopoietic cytokines and growth factors (e.g., FLT3 ligand, AXL, IL-3, GM-CSF, and FGF2) (25)(26)(27)(28)(29). Coculture of MOLM13 cells with HS5-GFP human bone marrow stromal cells (MSCs) induced a minimal 1.7-fold right shift in the TP-0903 IC 50 value compared with MOLM13 cells in culture alone, whereas a 4.9-and 2.5-fold right shift in IC 50 value was observed for gilteritinib and midostaurin, respectively ( Figure 4A and Supplemental Figure 8A).…”

Section: Resultsmentioning

confidence: 99%

TP-0903 is active in models of drug-resistant acute myeloid leukemia

et al. 2020

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Effective treatment for AML is challenging due to the presence of clonal heterogeneity and the evolution of polyclonal drug resistance. Here, we report that TP-0903 has potent activity against protein kinases related to STAT, AKT, and ERK signaling, as well as cell cycle regulators in biochemical and cellular assays. In vitro and in vivo, TP-0903 was active in multiple models of drug-resistant FLT3 mutant AML, including those involving the F691L gatekeeper mutation and bone marrow microenvironment–mediated factors. Furthermore, TP-0903 demonstrated preclinical activity in AML models with FLT3 -ITD and common co-occurring mutations in IDH2 and NRAS genes. We also showed that TP-0903 had ex vivo activity in primary AML cells with recurrent mutations including MLL -PTD, ASXL1 , SRSF2 , and WT1 , which are associated with poor prognosis or promote clinical resistance to AML-directed therapies. Our preclinical studies demonstrate that TP-0903 is a multikinase inhibitor with potent activity against multiple drug-resistant models of AML that will have an immediate clinical impact in a heterogeneous disease like AML.

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Section: Resultsmentioning

confidence: 99%

TP-0903 is active in models of drug-resistant acute myeloid leukemia

et al. 2020

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“…Since AML remains an incurable disease for the majority of patients, great efforts have focused to develop novel inhibitors during the last decade [ 201 ]. In this sense, CRISPR screening studies have helped to anticipate potential mechanisms of resistance for some of these new therapeutic approaches in AML [ 44 , 73 , 120 , 202 ].…”

Section: Mechanisms Of Drug Resistance Uncovered By Crispr High-throu...mentioning

confidence: 99%

“…Interestingly, the loss-of-function of the BAX gene has been commonly involved in venetoclax resistance in both CLL or AML diseases [ 63 , 72 ], DCK disruption in the resistance of cytarabine for AML or ALL [ 42 , 49 ] and CSN subunits of the CSN9 complex have been related with IMiDs resistance in MM or lymphoma [ 56 , 90 , 189 ]. Moreover, we can anticipate the resistance mechanisms of drugs under investigation through CRISPR approaches before their approval and the molecular characterization of a cohort of patients treated with novel drugs (for example, BET inhibitors, HSP90 inhibitors…) [ 44 , 73 , 120 , 202 ]. Taking into account that novel therapies are continuously emerging in hemato-oncology, we therefore envision that CRISPR screening will continue to have a role in the era of targeted therapy and immunotherapy.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

High-Throughput CRISPR Screening in Hematological Neoplasms

Ancos-Pintado

Bragado-García

Morales

et al. 2022

Cancers

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CRISPR is becoming an indispensable tool in biological research, revolutionizing diverse fields of medical research and biotechnology. In the last few years, several CRISPR-based genome-targeting tools have been translated for the study of hematological neoplasms. However, there is a lack of reviews focused on the wide uses of this technology in hematology. Therefore, in this review, we summarize the main CRISPR-based approaches of high throughput screenings applied to this field. Here we explain several libraries and algorithms for analysis of CRISPR screens used in hematology, accompanied by the most relevant databases. Moreover, we focus on (1) the identification of novel modulator genes of drug resistance and efficacy, which could anticipate relapses in patients and (2) new therapeutic targets and synthetic lethal interactions. We also discuss the approaches to uncover novel biomarkers of malignant transformations and immune evasion mechanisms. We explain the current literature in the most common lymphoid and myeloid neoplasms using this tool. Then, we conclude with future directions, highlighting the importance of further gene candidate validation and the integration and harmonization of the data from CRISPR screening approaches.

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“…In vitro studies using cell lines and xenograft models have validated their efficacy. Below, we have selected several studies [ 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 ] that have identified novel FLT3i with interesting efficacy and selectivity data, probably leading actors in future clinical trials. Table 3 summarizes the preclinical studies analyzing new compounds with their sensitivities and resistances.…”

Section: Flt3i: Indications Mechanisms Of Resistance In Vitro and In ...mentioning

confidence: 99%

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

Capelli

Menotti

Fiorentini

et al. 2022

Cancers

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FLT3 ITD and TKD mutations occur in 20% and 10% of Acute Myeloid Leukemia (AML), respectively, and they represent the target of the first approved anti-leukemic therapies in the 2000s. Type I and type II FLT3 inhibitors (FLT3i) are active against FLT3 TKD/ITD and FLT3 ITD mutations alone respectively, but they still fail remissions in 30–40% of patients due to primary and secondary mechanisms of resistance, with variable relapse rate of 30–50%, influenced by NPM status and FLT3 allelic ratio. Mechanisms of resistance to FLT3i have recently been analyzed through NGS and single cell assays that have identified and elucidated the polyclonal nature of relapse in clinical and preclinical studies, summarized here. Knowledge of tumor escape pathways has helped in the identification of new targeted drugs to overcome resistance. Immunotherapy and combination or sequential use of BCL2 inhibitors and experimental drugs including aurora kinases, menin and JAK2 inhibitors will be the goal of present and future clinical trials, especially in patients with FLT3-mutated (FLT3mut) AML who are not eligible for allogeneic transplantation.

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LAM-003, a new drug for treatment of tyrosine kinase inhibitor–resistant FLT3-ITD–positive AML

Abstract: Key Points The heat shock protein 90 inhibitor LAM-003 displays potent in vitro and in vivo activity as a single agent and combined with venetoclax. LAM-003 retains antileukemic activity against AML cells rendered resistant to FLT3 kinase inhibitors by mutation or stromal signaling.

Cited by 14 publications

References 69 publications

TP-0903 is active in models of drug-resistant acute myeloid leukemia

TP-0903 is active in models of drug-resistant acute myeloid leukemia

High-Throughput CRISPR Screening in Hematological Neoplasms

Overcoming Resistance: FLT3 Inhibitors Past, Present, Future and the Challenge of Cure

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