Investigation of CXCR7 signaling in EGFR TKI resistant NSCLC

EGFR TKI 耐药 NSCLC 中 CXCR7 信号传导的研究

基本信息

批准号：
10672451
负责人：
Takeshi Shimamura
金额：
$ 35.1万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-05 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10672451
关键词：
Automobile Driving Biological Markers Biological Process Biology CXC Chemokines Cancer Model Cancer Patient Cell Culture Techniques Cell Line Cells Clinical Clinical Research Complex Drug Targeting Drug Tolerance Drug resistance Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Epithelium Erlotinib Etiology Evolution G-Protein-Coupled Receptors Gefitinib Generations Genes Genetically Engineered Mouse Genomics Heterodimerization In Vitro Investigation Ligands Link Literature Maintenance Malignant Neoplasms Mediating Mesenchymal Modeling Molecular Mus Mutate Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Pathway interactions Patients Phenotype Prevalence Prognosis Proliferating Proteomics Public Health Receptor Inhibition Refractory Regulation Resistance Series Signal Transduction Snails Specimen Testing Therapeutic Transforming Growth Factor beta Transgenic Organisms Treatment Efficacy Tyrosine Kinase Inhibitor autocrine beta-arrestin cancer therapy cancer type chemokine receptor effective therapy epithelial to mesenchymal transition improved in vivo in vivo Model inhibitor inhibitor therapy lung cancer cell mouse model mutant new therapeutic target novel therapeutics overexpression patient derived xenograft model prevent prognostic resistance mechanism small hairpin RNA small molecule inhibitor targeted treatment therapeutic target tool transcription factor tumor

项目摘要

Although EGFR-targeted therapy significantly prolongs the survival of NSCLC patients with EGFR kinase domain activating mutations, acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) poses a significant clinical problem. Recent clinical studies demonstrated that an increasing number of these resistant NSCLCs undergo epithelial to mesenchymal transition (EMT); however, the molecular basis of acquired EGFR TKI with an EMT phenotype remains elusive. Consequently, patients with the acquired resistance do not benefit from effective therapies. We have demonstrated that the inhibition of mutant EGFR in NSCLC promotes TGFβ1-mediated EMT. In patient specimens, C-X-C chemokine receptor type 7 (CXCR7) is significantly upregulated in acquired EGFR TKI resistant NSCLC cells with an EMT phenotype. Prolonged depletion of CXCR7 with shRNA in the resistant cells not only restores epithelial phenotype but also sensitivity to EGFR TKIs. Our central hypothesis is that CXCR7 is a novel therapeutic target which promotes an EMT phenotype in EGFRmutant NSCLC and provides alternate survival/proliferation pathways when mutated-EGFR is inhibited. The overall objective is to determine the mechanism by which CXCR7 promotes EMT and thus resistance to EGFR TKI and determine whether CXCR7 is a superior drug target for NSCLC therapy. In Aim 1, we will determine the mechanism by which CXCR7 promotes survival of EGFR TKI resistant NSCLC. For this aim, we will investigate if a ligand activation of CXCR7 is required for the engagement of the resistant phenotype. Additionally, we will evaluate therapeutic approaches using in vitro and in vivo models to suppress CXCR7 signaling to specifically target EMT-associated NSCLC cells with EGFR-TKI resistance. In Aim 2, we will determine mechanisms responsible for EMT regulation by CXCR7 in NSCLC. To this end, we will investigate how CXCR7 activates downstream transcription factors to support EMT in EGFR mutant NSCLC by using genomics and proteomics approaches, cell culture and complementary transgenic murine EGFR mutant NSCLC models. In Aim 3, we will determine the therapeutic efficacy of targeting CXCR7 to eliminate EGFR TKI resistant cells with EMT. For this aim, we will investigate if EGFR TKI resistant cells with an EMT phenotype emerge through evolution from drug tolerant cells with increase expression of CXCR7 using PDX models and CXCR7 inhibitors. The results obtained from this proposal will facilitate the discovery of prognostic and therapeutic tools to inhibit CXCR7 expression leading to EGFR TKI resistance, to prevent the induction of EMT upon EGFR inhibition, and to provide a rationale to stratify NSCLC patients who become refractory to EGFR TKI with mesenchymal biomarkers for CXCR7-targeted therapeutics.

尽管EGFR靶向的治疗显着延长了NSCLC EGFR患者的存活率激酶结构域激活突变，获得了对EGFR酪氨酸激酶抑制剂（TKI）的抗性提出一个重大的临床问题。最近的临床研究表明，增加这些耐药的NSCLC的数量会经历间质转变（EMT）的上皮；然而，具有EMT表型的获得的EGFR TKI的分子基础仍然难以捉摸。最后，获得抗药性的患者不能受益于有效疗法。我们有证明突变EGFR在NSCLC中的抑制会促进TGFβ1介导的EMT。在患者标本，C-X-C趋化因子受体7型（CXCR7）在获得了具有EMT表型的EGFR TKI耐药NSCLC细胞。长时间的耗竭 CXCR7在抗性细胞中带有shRNA不仅恢复上皮表型，而且还恢复敏感性到EGFR TKIS。我们的中心假设是CXCR7是一个新型的治疗靶标的促进EGFRMUTANT NSCLC中的EMT表型，并提供替代的存活/增殖抑制突变-EGFR时的途径。总体目标是确定机制 CXCR7促进EMT并因此对EGFR TKI的抗性并确定CXCR7是否具有抗性是NSCLC治疗的卓越药物靶标。在AIM 1中，我们将确定该机制 CXCR7促进EGFR TKI耐药NSCLC的存活。为此，我们将调查是否 CXCR7的配体激活是抗性表型的参与所必需的。此外，我们将使用体外和体内模型评估治疗方法来抑制CXCR7 信号转导具有EGFR-TKI抗性的特异性靶向与EMT相关的NSCLC细胞。在AIM 2中，我们将确定NSCLC中CXCR7负责EMT调控的机制。为此，我们将研究CXCR7如何激活下游转录因子以支持EMT EGFR突变NSCLC通过使用基因组学和蛋白质组学方法，细胞培养和完全转基因鼠EGFR突变体NSCLC模型。在AIM 3中，我们将确定靶向CXCR7的治疗效率以消除具有EMT的EGFR TKI抗性细胞。为了这目的，我们将研究EGFR TKI抗EMT表型的抗性细胞是否通过使用PDX模型和 CXCR7抑制剂。从该提案中获得的结果将有助于发现预后以及抑制CXCR7表达的治疗工具，导致EGFR TKI抗性，以防止 EGFR抑制后EMT的诱导，并提供分层的NSCLC患者的理由用中充质生物标志物对CXCR7靶向疗法的EGFR TKI难治性。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Non-small cell lung carcinoma spheroid models in agarose microwells for drug response studies.

DOI：
10.1039/d2lc00244b
发表时间：
2022-06-14
期刊：
LAB ON A CHIP
影响因子：
6.1
作者：
Luan, Qiyue;Becker, Jeffrey H.;Macaraniag, Celine;Massad, Malek G.;Zhou, Jian;Shimamura, Takeshi;Papautsky, Ian
通讯作者：
Papautsky, Ian

In vivo metabolomics identifies CD38 as an emergent vulnerability in LKB1 -mutant lung cancer.

体内代谢组学将 CD38 确定为 LKB1 突变型肺癌中的一个新的脆弱性。

DOI：
10.1101/2023.04.18.537350
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Deng,Jiehui;Peng,DavidH;Fenyo,David;Yuan,Hao;Lopez,Alfonso;Levin,DanielS;Meynardie,Mary;Quinteros,Mari;Ranieri,Michela;Sahu,Soumyadip;Lau,SallyCM;Shum,Elaine;Velcheti,Vamsidhar;Punekar,SalmanR;Rekhtman,Natasha;Dowling,C
通讯作者：
Dowling,C

Heterogeneity in Tumors and Resistance to EGFR TKI Therapy-Response.

肿瘤的异质性和对 EGFR TKI 治疗反应的耐药性。