The EGFR TKI plays an important role in the treatment of lung adenocarcinoma. The prognosis was affected by the drug resistance to EGFR TKI and the mechanism is still unclear. Some recent reports have showed that the hypoxia contributes to the acquired resistance of EGFR TKI in lung adenocarcinoma. Our previous study found that formyl peptide receptor 1 (FPR1) expressed higher in the erlotinib resistant lung adenocarcinoma cell lines which we have established and FPR1 could activate the ERK pathway through cross talk with the EGFR. IC50 can be higher when plus agonist while lower with antagonist. Then we observed that hypoxia could induce the expression of FPR1 and the FPR1 promoter regions have HIF1α binding sites. So we build a hypothesis that the hypoxic microenvironment could induce the expression of HIF1α and FPR1. Then activate the ERK pathway and induce the acquired drug resistance of EGFR TKI. In this proposal we will analyze the changes of FPR 1, ERK pathway and drug sensitivity with EGFR TKI of lung adenocarcinoma cell line in the hypoxic microenvironment. We will comfirm the role of hypoxia with the acquired erlotinib resistance by overexpressing and silencing HIF1α and FPR1 gene expression. Moreover we will clarify the mechanism that the activation of ERK pathway by FPR1 could make the resistance to EGFR TKI in lung adenocarcinoma. This research will find a new target for overcoming the acquired resistance of EGFR-TKI in lung adenocarcinoma.
肺癌分子靶向治疗耐药严重影响患者预后,近年报道缺氧与肺腺癌表皮生长因子受体酪氨酸激酶抑制剂(EGFR TKI)获得性耐药相关,但机制有待探讨。我们前期发现肺腺癌细胞株HCC827厄洛替尼耐药株高表达甲酰肽受体1 (FPR1),可激活ERK通路并与厄洛替尼耐药相关;还发现缺氧条件下培养可诱导细胞高表达FPR1及缺氧诱导因子1α(HIF1α);通过生物信息学软件预测发现FPR1启动子区域有HIF1α的结合位点。因此提出肺腺癌在缺氧微环境下通过HIF1α促进FPR1表达并激活FPR1-ERK通路是其产生EGFR TKI耐药性的科学假设。拟在发现FPR1与厄洛替尼耐药相关的基础上,体内外实验研究缺氧对肺腺癌FPR1的表达、ERK通路的活化以及厄洛替尼耐药性的影响,以明确肺癌在缺氧微环境中激活FPR1-ERK通路继而获得EGFR TKI耐药性,为深入理解耐药机制和寻找新靶点提供新的实验依据。
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数据更新时间:2023-05-31
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