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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Frontiers Media S.A.
2021-11-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.782065/full |
| _version_ | 1818894493859971072 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T18:29:23Z |
| format | Article |
| id | doaj.art-0a92459ad95f4317b33426f7bd48c01c |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-19T18:29:23Z |
| publishDate | 2021-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-0a92459ad95f4317b33426f7bd48c01c2022-12-21T20:10:46ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-11-011110.3389/fonc.2021.782065782065LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling PathwayAmin Huang0Peiting Zeng1Yinguang Li2Wenhua Lu3Yaoming Lai4Department of Medical Oncology of the East Division, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, ChinaState Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, ChinaDepartment of Obstetrics and Gynecology of the East Division, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, ChinaState Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, ChinaDepartment of Rehabilitation, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, ChinaInternal 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.https://www.frontiersin.org/articles/10.3389/fonc.2021.782065/fullFMS-like tyrosine kinase 3Internal tandem duplicationLY294002Drug resistanceAcute myeloid leukemiaPI3K/Akt |
| spellingShingle | 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 Frontiers in Oncology FMS-like tyrosine kinase 3 Internal tandem duplication LY294002 Drug resistance Acute myeloid leukemia PI3K/Akt |
| title | 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_short | 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 |
| topic | FMS-like tyrosine kinase 3 Internal tandem duplication LY294002 Drug resistance Acute myeloid leukemia PI3K/Akt |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.782065/full |
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