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Explore the signaling mechanisms of acquired resistance to tyrosine kinase inhibitors in AML

探索 AML 中酪氨酸激酶抑制剂获得性耐药的信号机制

基本信息

批准号：
10363682
负责人：
Jian Huang
金额：
$ 40.04万
依托单位：
CORIELL INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-03 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10363682
关键词：
Acute Myelocytic Leukemia Acute leukemia Adult Biochemical Genetics Blood Bone Marrow Diseases CRISPR screen Cell Survival Cells Clinic Clinical Clinical Research Clinical Treatment Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Cytokine Receptors DNA Sequence Alteration Data Development Disease Drug resistance FLT3 gene Family Generations Genes Genetic Screening Goals Hematological Disease Hematopoiesis Hematopoietic Knock-out Knowledge Lead Libraries Life Link MAP Kinase Gene MEKs Maintenance Therapy Malignant - descriptor Mediator of activation protein Mitogen-Activated Protein Kinases Molecular Molecular Abnormality Mutate Mutation Pathway interactions Patients Pharmaceutical Preparations Play Positioning Attribute Prognosis Protein Tyrosine Kinase Proteins Receptor Protein-Tyrosine Kinases Refractory Regimen Relapse Reporting Resistance Role Sampling Series Signal Pathway Signal Transduction Testing Therapeutic Translating Tyrosine Kinase Inhibitor WNT Signaling Pathway acquired drug resistance acute myeloid leukemia cell antagonist base beta catenin cell growth clinically relevant genetic approach in vivo inhibitor inhibitor therapy insight kinase inhibitor leukemia loss of function member mouse model new therapeutic target novel receptor resistance mechanism response small molecule success targeted treatment translational potential

项目摘要

Explore the signaling mechanisms of acquired resistance to tyrosine kinase inhibitors in AML Abstract Acute myeloid leukemia (AML) is a malignant hematopoietic disease and the most common type of acute leukemia in adults. One major obstacle to greater success with target therapy of leukemia is drug resistance. The mechanisms underlying drug resistance in AML are poorly understood. FLT3 is a cytokine receptor which belongs to the receptor tyrosine kinase (RTK) class III. Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are now recognized as the most common molecular abnormality in AML and FLT3ITD mutations are found in nearly 30% of AML patients. Quizartinib (AC220) is a potent and selective second-generation inhibitor of FLT3. It is in clinical trials for the treatment of relapsed or refractory FLT3ITD positive and negative AML patients and as maintenance therapy. Remarkably, those clinical trials have showed very promising result. However, drug resistance to AC220 has also been reported through the early clinical studies. To understand the underlying mechanisms of drug resistance to AC220, we undertook an unbiased approach with a novel CRISPR pooled library to screen new genes whose loss of function confers resistance to AC220. In our screen, we identified SPRY3, an intracellular inhibitor of RTK signaling, and GSK3, a canonical Wnt signaling antagonist, and demonstrated that re-activation of downstream RTK/Ras/ERK and Wnt signaling as major mechanisms of resistance to the FLT3 inhibitor. Furthermore, we also confirmed our findings in primary AML patient samples. We demonstrated that the expression level of SPRY3 and GSK3A is dramatically reduced in AC220 resistant AML samples and SPRY3 deleted primary AML cells are resistant to AC220. Additionally, we treated SPRY3 and GSK3 knockout AML cells with a potent MAP kinase inhibitor and β- catenin inhibitor respectively, demonstrated that both inhibitors re-sensitized AML cells to AC220. Intriguingly, we found that expression of SPRY3 is greatly reduced in GSK3 knockout AML cells, which positioned SPRY3 downstream of GSK3 in the resistance pathway. In this proposal, we hypothesize that Sprouty (SPRY) and GSK3 play critical roles in the response to tyrosine kinase inhibitor in AML. The Ras/MEK/ERK and Wnt pathways regulated by SPRY3 and GSK3 are important for the acquired drug resistance in AML. Next, we will perform a series comprehensive study to explore novel downstream effectors/ interacting partners of SPRY3 and GSK3 in AMLs and the molecular mechanisms of their action. Furthermore, we will examine the possibility to translate our findings into new clinical therapies. Taken together, our study identified novel genes whose loss of function confers resistance to a selective FLT3 inhibitor and revealed the underlying mechanism, thereby providing new insight into signaling pathways that contribute to the acquired resistance in AML. The knowledge learned may lead to the development of more efficient combined therapeutic avenues for AML.

探讨AML获得性对酪氨酸激酶抑制剂耐药的信号机制