LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway

Internal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid leukemia (AML) patients, always predicts a poor prognosis. As a small molecule tyrosine kinase inhibitor, sorafenib is clinically used for the treatmen...

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Autores principales:	Amin Huang, Peiting Zeng, Yinguang Li, Wenhua Lu, Yaoming Lai
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	FMS-like tyrosine kinase 3 Internal tandem duplication LY294002 Drug resistance Acute myeloid leukemia PI3K/Akt Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/0a92459ad95f4317b33426f7bd48c01c
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spelling	oai:doaj.org-article:0a92459ad95f4317b33426f7bd48c01c2021-11-08T06:41:27ZLY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway2234-943X10.3389/fonc.2021.782065https://doaj.org/article/0a92459ad95f4317b33426f7bd48c01c2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.782065/fullhttps://doaj.org/toc/2234-943XInternal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid leukemia (AML) patients, always predicts a poor prognosis. As a small molecule tyrosine kinase inhibitor, sorafenib is clinically used for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and differentiated thyroid cancer (DTC), with its preclinical and clinical activity demonstrated in the treatment of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant AML. Even though it shows a rosy future in the AML treatment, the short response duration remains a vital problem that leads to treatment failure. Rapid onset of drug resistance is still a thorny problem that we cannot overlook. Although the mechanisms of drug resistance have been studied extensively in the past years, there is still no consensus on the exact reason for resistance and without effective therapeutic regimens established clinically. My previous work reported that sorafenib-resistant FLT3-ITD mutant AML cells displayed mitochondria dysfunction, which rendered cells depending on glycolysis for energy supply. In my present one, we further illustrated that losing the target protein FLT3 and the continuously activated PI3K/Akt signaling pathway may be the reason for drug resistance, with sustained activation of PI3K/AKT signaling responsible for the highly glycolytic activity and adenosine triphosphate (ATP) generation. PI3K inhibitor, LY294002, can block PI3K/AKT signaling, further inhibit glycolysis to disturb ATP production, and finally induce cell apoptosis. This finding would pave the way to remedy the FLT3-ITD mutant AML patients who failed with FLT3 targeted therapy.Amin HuangPeiting ZengYinguang LiWenhua LuYaoming LaiFrontiers Media S.A.articleFMS-like tyrosine kinase 3Internal tandem duplicationLY294002Drug resistanceAcute myeloid leukemiaPI3K/AktNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	FMS-like tyrosine kinase 3 Internal tandem duplication LY294002 Drug resistance Acute myeloid leukemia PI3K/Akt Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	FMS-like tyrosine kinase 3 Internal tandem duplication LY294002 Drug resistance Acute myeloid leukemia PI3K/Akt Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Amin Huang Peiting Zeng Yinguang Li Wenhua Lu Yaoming Lai LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway
description	Internal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid leukemia (AML) patients, always predicts a poor prognosis. As a small molecule tyrosine kinase inhibitor, sorafenib is clinically used for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and differentiated thyroid cancer (DTC), with its preclinical and clinical activity demonstrated in the treatment of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant AML. Even though it shows a rosy future in the AML treatment, the short response duration remains a vital problem that leads to treatment failure. Rapid onset of drug resistance is still a thorny problem that we cannot overlook. Although the mechanisms of drug resistance have been studied extensively in the past years, there is still no consensus on the exact reason for resistance and without effective therapeutic regimens established clinically. My previous work reported that sorafenib-resistant FLT3-ITD mutant AML cells displayed mitochondria dysfunction, which rendered cells depending on glycolysis for energy supply. In my present one, we further illustrated that losing the target protein FLT3 and the continuously activated PI3K/Akt signaling pathway may be the reason for drug resistance, with sustained activation of PI3K/AKT signaling responsible for the highly glycolytic activity and adenosine triphosphate (ATP) generation. PI3K inhibitor, LY294002, can block PI3K/AKT signaling, further inhibit glycolysis to disturb ATP production, and finally induce cell apoptosis. This finding would pave the way to remedy the FLT3-ITD mutant AML patients who failed with FLT3 targeted therapy.
format	article
author	Amin Huang Peiting Zeng Yinguang Li Wenhua Lu Yaoming Lai
author_facet	Amin Huang Peiting Zeng Yinguang Li Wenhua Lu Yaoming Lai
author_sort	Amin Huang
title	LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway
title_short	LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway
title_full	LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway
title_fullStr	LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway
title_full_unstemmed	LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway
title_sort	ly294002 is a promising inhibitor to overcome sorafenib resistance in flt3-itd mutant aml cells by interfering with pi3k/akt signaling pathway
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/0a92459ad95f4317b33426f7bd48c01c
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LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway

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