CN111358794A - 一种用于治疗非小细胞肺癌的药物或试剂盒 - Google Patents
一种用于治疗非小细胞肺癌的药物或试剂盒 Download PDFInfo
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Abstract
本发明公开KRASG12C抑制剂和FGFR1抑制剂的联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用;本发明还公开KRASG12C抑制剂和MEK抑制剂的联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用;本发明还公开一种用于治疗非小细胞肺癌的药物或试剂盒,包括KRASG12C抑制剂ARS‑1620、及与KRASG12C抑制剂ARS‑1620联合使用的FGFR1抑制剂AZD4547或MEK抑制剂PD032590中的一种。本发明联合使用ARS‑1620和FGFR1抑制剂AZD4547,或联合使用ARS‑1620和MEK抑制剂PD032590,均能显著增强杀伤作用,而且能够抑制耐药产生,为非小细胞肺癌的治疗提供有效的治疗药物和治疗方向。
Description
技术领域
本发明属于生物医疗技术领域,具体涉及一种用于治疗非小细胞肺癌的药物或试剂盒。
背景技术
肺癌中大多数为非小细胞肺癌(NSCLC),其中约30%的患者携带促癌的KRAS基因突变。KRAS基因突变最常见类型是第12位氨基酸G→C突变(KRASG12C),该突变导致肺癌的分子机制是过度激活了MAPK信号通路(即KRAS/RAF/MEK/ERK级联信号通路)。体外研究发现,KRASG12C抑制剂虽然可以特异性杀伤KRASG12C的肺癌细胞株,但效果维持时间短,细胞能快速产生耐药。目前尚缺乏高效特异的方法或药物来杀伤KRASG12C细胞,同时能够抑制耐药的出现。
发明内容
本发明要解决的技术问题是提供用于治疗非小细胞肺癌的药物或试剂盒,能够抑制耐药的出现,以解决背景技术中所提出的问题。
本发明的实施例提供KRASG12C抑制剂和FGFR1抑制剂的联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用。
进一步的,所述KRASG12C抑制剂为ARS-1620。
进一步的,所述FGFR1抑制剂为AZD4547。
本发明的实施例还提供KRASG12C抑制剂和MEK抑制剂联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用。
其中,所述KRASG12C抑制剂为ARS-1620。
其中,所述MEK抑制剂为PD032590。
本发明的实施例还提供一种用于治疗非小细胞肺癌的药物,其特征在于,包括KRASG12C抑制剂ARS-1620、与KRASG12C抑制剂ARS-1620联合使用的FGFR1抑制剂AZD4547或MEK抑制剂PD032590中的一种。
本发明的实施例还一种用于治疗非小细胞肺癌的试剂盒,其特征在于,包括KRASG12C抑制剂ARS-1620、与KRASG12C抑制剂ARS-1620联合使用的FGFR1抑制剂AZD4547或MEK抑制剂PD032590中的一种。
本发明的实施例另外还提供一种用于治疗非小细胞肺癌的药物或试剂盒的耐药性的检测方法,其特征在于,具体包括以下步骤:
(1)在96孔细胞培养板中培养携带KRASG12C突变的细胞株H23,Calu-1,H358;
(2)在步骤(1)所制备完成的96孔细胞培养板中,使用FGFR1抑制剂AZD4547单独进行处理103H358-P或H358-R细胞;72小时后用CCK8细胞增殖实验检测对细胞的杀伤作用,然后持续用药,观察耐药出现的时间;
(3)在步骤(1)所制备完成的96孔细胞培养板中,用1μM FGFR1抑制剂AZD4547与1μM的ARS-1620联合使用或100nM MEK抑制剂PD032590与100nM的ARS-1620联合使用进行处理103H358-P或H358-R细胞,72小时后用CCK8细胞增殖实验检测对细胞的杀伤作用,然后持续用药,观察耐药出现的时间;
(4)比较步骤(2)和步骤(3)中耐药出现的时间,从而验证试剂盒的耐药性。
本发明的上述技术方案的有益效果如下:本发明针对KRASG12C抑制剂ARS-1620对敏感细胞只有短暂的抑制作用,很容易诱导耐药的问题,研究了耐药的机制介导,可以发现由以下两个机制介导:FGFR1基因高表达或MAPK信号通路重激活;因此,本发明联合使用ARS-1620和FGFR1抑制剂AZD4547,或联合使用ARS-1620和MEK抑制剂PD032590,均能显著增强杀伤作用,而且能够抑制耐药产生,为非小细胞肺癌的治疗提供有效的治疗药物和治疗方向。
附图说明
图1为本发明中的实施例1中使用1μM ARS-1620处理Calu-1、H23、H358细胞,72h后检测细胞的存活率情况图;
图2为本发明中的实施例1中FGFR1在H358-P和H358-R中的表达情况图;
图3为本发明中的实施例1中1μM ARS-1620和1μM AZD4547联合处理H358-P和H358-R细胞,72h后检测存活率情况图;
图4为本发明中的实施例2中1μM ARS-1620处理H358细胞不同时间后,检测ERK,p-ERK和内参Vinculin的表达图;其中,p-ERK的表达水平代表了MAPK信号通路的激活程度;
图5为本发明中的实施例2中100nM ARS-1620和100nM PD0325901联合处理H358-P和H358-R细胞,72h后检测存活率图。
具体实施方式
为使本发明要解决的技术问题、技术方案和优点更加清楚,下面将结合附图及具体实施例进行详细描述。
一、本发明的实施例中所用实验材料来源:
ARS-162购自美国Selleck公司,货号S8707;
AZD4547购自美国Selleck公司,货号S2801;
PD0325901购自美国MCE公司,货号HY-10254;
H23,Calu-1和H358肺癌细胞株均购自美国ATCC公司(American Type CultureCollection)公司,南通大学医学院免疫学系保存。
二、本发明分别在多个96孔细胞培养板中培养携带KRASG12C突变的细胞株H23,Calu-1,H358,便于以下实施例中实验的操作。
实施例一
ARS-1620和AZD4547联合处理、效果分析:
(1)KRASG12C抑制剂ARS-1620处理
(1-1)在96孔细胞培养板中,用1μM的KRASG12C抑制剂ARS-1620处理103细胞(104/ml),72小时后CCK8细胞增殖实验方法检测细胞对药物的敏感性,获得最敏感细胞株H358作为细胞模型(图1)。
(1-2)继续用1μM的KRASG12C抑制剂ARS-1620处理H358细胞2周,期间每2天换液去除死细胞,2周后细胞恢复增殖速度,获得ARS-1620耐受的H358细胞(H358-R)。
(1-3)收集2×106未处理的亲本的H358细胞(H358-P)和2×106H358-R细胞,用Trizol法提取细胞的RNA,然后用RNA测序的方法获得转录组数据,其中包含了细胞内所有基因的表达水平,结果显示3421个基因在H358-R中比H358-P中表达升高,2723个基因表达下降。
(1-4)仔细分析H358-P和H358-R的转录组,发现在升高的基因中,FGFR1的表达增加特别显著(如图2所示),提示FGFR1可能是诱导耐药的关键因素。
(2)1μM FGFR1抑制剂AZD4547和1μM的ARS-1620同时处理
(2-1)在96孔细胞培养板中,用1μM FGFR1抑制剂AZD4547和1μM的ARS-1620同时处理103H358-P或H358-R细胞(104/ml),72小时后用CCK8细胞增殖实验检测对细胞的杀伤作用。
(3)结果分析
结果证实H358-R细胞完全耐受双药的联合处理,但H358-P对双药联合处理极其敏感(如图3所示),而且培养4周没有耐药,这与ARS-1620单药后快速出现耐药形成显著对比。
实施例二
(4)ARS-1620和PD0325901联合使用、效果分析:
在96孔细胞培养板中,用1μM ARS-1620处理2×106H358细胞6小时,12小时,24小时,48小时,18天,42天,用Western blot分析MAPK信号通路,发现耐药的细胞(D18,D42)的p-ERK显著增加,提示MAPK信号通路增强(如图4所示)。
在96孔细胞培养板中,用100nM MEK抑制剂PD0325901(抑制MAPK通路)和100nM的ARS-1620同时处理1×103H358-P或H358-R细胞(104/ml),72小时后用CCK8细胞增殖实验检测药物对细胞的杀伤作用。
结果证实H358-R细胞完全耐受双药的联合处理,但H358-P对双药处理极其敏感(如图5所示),而且培养4周没有耐药,这与ARS-1620单药后快速出现耐药形成显著对比。
更进一步的,本发明提出对于敏感的细胞先用ARS-1620单药处理,一旦耐药,对ARS-1620和FGFR1抑制剂AZD4547,ARS-1620和MEK抑制剂PD032590联合处理也耐药,因此,本发明提出对敏感的细胞必须直接采取联合处理。
以上所述是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明所述原理的前提下,还可以作出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.KRASG12C抑制剂和FGFR1抑制剂的联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用。
2.根据权利要求1所述的KRASG12C抑制剂和FGFR1抑制剂的联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用,其特征在于,所述KRASG12C抑制剂为ARS-1620。
3.根据权利要求1所述的KRASG12C抑制剂和FGFR1抑制剂的联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用,其特征在于,所述FGFR1抑制剂为AZD4547。
4.KRASG12C抑制剂和MEK抑制剂联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用。
5.根据权利要求4所述的KRASG12C抑制剂和MEK抑制剂的联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用,其特征在于,所述KRASG12C抑制剂为ARS-1620。
6.根据权利要求4所述的KRASG12C抑制剂和MEK抑制剂的联合使用在制备治疗非小细胞肺癌药物或试剂盒方面的应用,其特征在于,所述MEK抑制剂为PD032590。
7.一种用于治疗非小细胞肺癌的药物,其特征在于,包括KRASG12C抑制剂ARS-1620、与KRASG12C抑制剂ARS-1620联合使用的FGFR1抑制剂AZD4547或MEK抑制剂PD032590中的一种。
8.一种用于治疗非小细胞肺癌的试剂盒,其特征在于,包括KRASG12C抑制剂ARS-1620、与KRASG12C抑制剂ARS-1620联合使用的FGFR1抑制剂AZD4547或MEK抑制剂PD032590中的一种。
9.一种根据权利要求7或8所述的用于治疗非小细胞肺癌的药物或试剂盒的耐药性的检测方法,其特征在于,具体包括以下步骤:
(1)在96孔细胞培养板中培养携带KRASG12C突变的细胞株H23,Calu-1,H358;
(2)在步骤(1)所制备完成的96孔细胞培养板中,使用FGFR1抑制剂AZD4547单独进行处理103H358-P或H358-R细胞;72小时后用CCK8细胞增殖实验检测对细胞的杀伤作用,然后持续用药,观察耐药出现的时间;
(3)在步骤(1)所制备完成的96孔细胞培养板中,用1μM FGFR1抑制剂AZD4547与1μM的ARS-1620联合使用或100nM MEK抑制剂PD032590与100nM的ARS-1620联合使用进行处理103H358-P或H358-R细胞,72小时后用CCK8细胞增殖实验检测对细胞的杀伤作用,然后持续用药,观察耐药出现的时间;
(4)比较步骤(2)和步骤(3)中耐药出现的时间,从而验证药物或试剂盒的耐药性。
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