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Sci Rep：ALK阳性非小细胞肺癌中双重抑制ALK和MEK抑制细胞生长的机制

2019-12-20 xiangting MedSci原创

ALk阳性非小细胞肺癌MEK抑制剂ALK抑制剂司美替尼
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研究结果支持以下假设：MEK抑制剂与ALK抑制剂联合使用可以克服ALK抑制剂耐药，并将Bim、PARP和CDK1确定为可能三联药物治疗的药物靶标。

间变性淋巴瘤激酶（ALK）重排，使得细胞对ALK酪氨酸激酶抑制剂（TKIs）敏感，是一小部分非小细胞肺癌的关键致癌驱动因素。第一代ALK-TKI克唑替尼优于标准化疗，其无进展生存期更长并且客观应答率更高。但是，临床获益通常在治疗一年内受到耐药性的限制。

这项研究探讨了克唑替尼和MEK抑制剂司美替尼在克唑替尼初治（H3122）和克唑替尼耐药（CR-H3122）ALK阳性肺癌细胞中的联合作用。

结果表明，由于下游RAS/MAPK信号传导被抑制，导致细胞凋亡增加和细胞增殖减少，从而联合治疗有效抑制了H3122和CR-H3122细胞的生长。与克唑替尼单药治疗相比，药物联合还引起Bim（细胞凋亡的中介）和p27（细胞周期蛋白依赖性激酶抑制剂）升高3倍以上。

研究结果支持以下假设：MEK抑制剂与ALK抑制剂联合使用可以克服ALK抑制剂耐药，并将Bim、PARP和CDK1确定为可能三联药物治疗的药物靶标。

原始出处：

N. Shrestha. Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer. Sci Rep. 11 December 2019.

本文系梅斯医学(MedSci)原创编译整理，转载需授权！

 

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  1. [GetPortalCommentsPageByObjectIdResponse(id=2059856, encodeId=98092059856c9, content=<a href='/topic/show?id=2cc599381bd' target=_blank style='color:#2F92EE;'>#非小细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=99381, encryptionId=2cc599381bd, topicName=非小细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e07307, createdName=lingaifan, createdTime=Tue Feb 04 17:14:00 CST 2020, time=2020-02-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943906, encodeId=ed4819439063a, content=<a href='/topic/show?id=d2af1152597' target=_blank style='color:#2F92EE;'>#MEK#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11525, encryptionId=d2af1152597, topicName=MEK)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5b0e350, createdName=naiwu77, createdTime=Thu Jan 09 15:14:00 CST 2020, time=2020-01-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1987548, encodeId=22bb198e54892, content=<a href='/topic/show?id=540623233e' target=_blank style='color:#2F92EE;'>#ALK阳性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2323, encryptionId=540623233e, topicName=ALK阳性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, createdName=xjy02, createdTime=Fri Oct 16 11:14:00 CST 2020, time=2020-10-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1984833, encodeId=ce0119848336a, content=<a href='/topic/show?id=f7f5232e03' target=_blank style='color:#2F92EE;'>#ALk阳性非小细胞肺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2327, encryptionId=f7f5232e03, topicName=ALk阳性非小细胞肺癌)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/fa8I6JticHgohY5FSGE98I1F4gpCjrpl2nbN6jZJY6JEqAjUibjItOA9AsgbBwTuBzAPbU5Tl8DxfemWUFFzBOYw/132, createdBy=24c12500054, createdName=ms2186806800017884, createdTime=Wed Oct 28 11:14:00 CST 2020, time=2020-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2045850, encodeId=abe72045850de, content=<a href='/topic/show?id=ecf49e5173d' target=_blank style='color:#2F92EE;'>#阳性非小细胞肺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97517, encryptionId=ecf49e5173d, topicName=阳性非小细胞肺癌)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1a19115, createdName=stfoxst, createdTime=Tue Nov 03 15:14:00 CST 2020, time=2020-11-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1569044, encodeId=f2c41569044bf, content=<a href='/topic/show?id=5b9ee7968f5' target=_blank style='color:#2F92EE;'>#细胞生长#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77968, encryptionId=5b9ee7968f5, topicName=细胞生长)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=75d615484024, createdName=wwzzly, createdTime=Sun Dec 22 03:14:00 CST 2019, time=2019-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1039172, encodeId=022210391e2df, content=机制研究离临床仍然有距离，不过与临床结合思考，仍然有帮助的，不能仅仅是纯临床思维，转化思维同样重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=肿肿, createdTime=Fri Dec 20 15:14:00 CST 2019, time=2019-12-20, status=1, ipAttribution=)]
    2020-02-04 lingaifan

    #非小细胞#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=2059856, encodeId=98092059856c9, content=<a href='/topic/show?id=2cc599381bd' target=_blank style='color:#2F92EE;'>#非小细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=99381, encryptionId=2cc599381bd, topicName=非小细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e07307, createdName=lingaifan, createdTime=Tue Feb 04 17:14:00 CST 2020, time=2020-02-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943906, encodeId=ed4819439063a, content=<a href='/topic/show?id=d2af1152597' target=_blank style='color:#2F92EE;'>#MEK#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11525, encryptionId=d2af1152597, topicName=MEK)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5b0e350, createdName=naiwu77, createdTime=Thu Jan 09 15:14:00 CST 2020, time=2020-01-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1987548, encodeId=22bb198e54892, content=<a href='/topic/show?id=540623233e' target=_blank style='color:#2F92EE;'>#ALK阳性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2323, encryptionId=540623233e, topicName=ALK阳性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, createdName=xjy02, createdTime=Fri Oct 16 11:14:00 CST 2020, time=2020-10-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1984833, encodeId=ce0119848336a, content=<a href='/topic/show?id=f7f5232e03' target=_blank style='color:#2F92EE;'>#ALk阳性非小细胞肺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2327, encryptionId=f7f5232e03, topicName=ALk阳性非小细胞肺癌)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/fa8I6JticHgohY5FSGE98I1F4gpCjrpl2nbN6jZJY6JEqAjUibjItOA9AsgbBwTuBzAPbU5Tl8DxfemWUFFzBOYw/132, createdBy=24c12500054, createdName=ms2186806800017884, createdTime=Wed Oct 28 11:14:00 CST 2020, time=2020-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2045850, encodeId=abe72045850de, content=<a href='/topic/show?id=ecf49e5173d' target=_blank style='color:#2F92EE;'>#阳性非小细胞肺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97517, encryptionId=ecf49e5173d, topicName=阳性非小细胞肺癌)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1a19115, createdName=stfoxst, createdTime=Tue Nov 03 15:14:00 CST 2020, time=2020-11-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1569044, encodeId=f2c41569044bf, content=<a href='/topic/show?id=5b9ee7968f5' target=_blank style='color:#2F92EE;'>#细胞生长#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77968, encryptionId=5b9ee7968f5, topicName=细胞生长)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=75d615484024, createdName=wwzzly, createdTime=Sun Dec 22 03:14:00 CST 2019, time=2019-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1039172, encodeId=022210391e2df, content=机制研究离临床仍然有距离，不过与临床结合思考，仍然有帮助的，不能仅仅是纯临床思维，转化思维同样重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=肿肿, createdTime=Fri Dec 20 15:14:00 CST 2019, time=2019-12-20, status=1, ipAttribution=)]
    2020-01-09 naiwu77

    #MEK#

    0

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    2020-10-16 xjy02

    #ALK阳性#

    0

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    2020-10-28 ms2186806800017884

    #ALk阳性非小细胞肺癌#

    0

  5. [GetPortalCommentsPageByObjectIdResponse(id=2059856, encodeId=98092059856c9, content=<a href='/topic/show?id=2cc599381bd' target=_blank style='color:#2F92EE;'>#非小细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=99381, encryptionId=2cc599381bd, topicName=非小细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e07307, createdName=lingaifan, createdTime=Tue Feb 04 17:14:00 CST 2020, time=2020-02-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943906, encodeId=ed4819439063a, content=<a href='/topic/show?id=d2af1152597' target=_blank style='color:#2F92EE;'>#MEK#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11525, encryptionId=d2af1152597, topicName=MEK)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5b0e350, createdName=naiwu77, createdTime=Thu Jan 09 15:14:00 CST 2020, time=2020-01-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1987548, encodeId=22bb198e54892, content=<a href='/topic/show?id=540623233e' target=_blank style='color:#2F92EE;'>#ALK阳性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2323, encryptionId=540623233e, topicName=ALK阳性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, createdName=xjy02, createdTime=Fri Oct 16 11:14:00 CST 2020, time=2020-10-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1984833, encodeId=ce0119848336a, content=<a href='/topic/show?id=f7f5232e03' target=_blank style='color:#2F92EE;'>#ALk阳性非小细胞肺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2327, encryptionId=f7f5232e03, topicName=ALk阳性非小细胞肺癌)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/fa8I6JticHgohY5FSGE98I1F4gpCjrpl2nbN6jZJY6JEqAjUibjItOA9AsgbBwTuBzAPbU5Tl8DxfemWUFFzBOYw/132, createdBy=24c12500054, createdName=ms2186806800017884, createdTime=Wed Oct 28 11:14:00 CST 2020, time=2020-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2045850, encodeId=abe72045850de, content=<a href='/topic/show?id=ecf49e5173d' target=_blank style='color:#2F92EE;'>#阳性非小细胞肺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97517, encryptionId=ecf49e5173d, topicName=阳性非小细胞肺癌)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1a19115, createdName=stfoxst, createdTime=Tue Nov 03 15:14:00 CST 2020, time=2020-11-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1569044, encodeId=f2c41569044bf, content=<a href='/topic/show?id=5b9ee7968f5' target=_blank style='color:#2F92EE;'>#细胞生长#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77968, encryptionId=5b9ee7968f5, topicName=细胞生长)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=75d615484024, createdName=wwzzly, createdTime=Sun Dec 22 03:14:00 CST 2019, time=2019-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1039172, encodeId=022210391e2df, content=机制研究离临床仍然有距离，不过与临床结合思考，仍然有帮助的，不能仅仅是纯临床思维，转化思维同样重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=肿肿, createdTime=Fri Dec 20 15:14:00 CST 2019, time=2019-12-20, status=1, ipAttribution=)]
    2020-11-03 stfoxst

    #阳性非小细胞肺癌#

    0

  6. [GetPortalCommentsPageByObjectIdResponse(id=2059856, encodeId=98092059856c9, content=<a href='/topic/show?id=2cc599381bd' target=_blank style='color:#2F92EE;'>#非小细胞#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=99381, encryptionId=2cc599381bd, topicName=非小细胞)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=2e07307, createdName=lingaifan, createdTime=Tue Feb 04 17:14:00 CST 2020, time=2020-02-04, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1943906, encodeId=ed4819439063a, content=<a href='/topic/show?id=d2af1152597' target=_blank style='color:#2F92EE;'>#MEK#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=40, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=11525, encryptionId=d2af1152597, topicName=MEK)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=5b0e350, createdName=naiwu77, createdTime=Thu Jan 09 15:14:00 CST 2020, time=2020-01-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1987548, encodeId=22bb198e54892, content=<a href='/topic/show?id=540623233e' target=_blank style='color:#2F92EE;'>#ALK阳性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2323, encryptionId=540623233e, topicName=ALK阳性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d59291, createdName=xjy02, createdTime=Fri Oct 16 11:14:00 CST 2020, time=2020-10-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1984833, encodeId=ce0119848336a, content=<a href='/topic/show?id=f7f5232e03' target=_blank style='color:#2F92EE;'>#ALk阳性非小细胞肺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=2327, encryptionId=f7f5232e03, topicName=ALk阳性非小细胞肺癌)], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/fa8I6JticHgohY5FSGE98I1F4gpCjrpl2nbN6jZJY6JEqAjUibjItOA9AsgbBwTuBzAPbU5Tl8DxfemWUFFzBOYw/132, createdBy=24c12500054, createdName=ms2186806800017884, createdTime=Wed Oct 28 11:14:00 CST 2020, time=2020-10-28, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2045850, encodeId=abe72045850de, content=<a href='/topic/show?id=ecf49e5173d' target=_blank style='color:#2F92EE;'>#阳性非小细胞肺癌#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97517, encryptionId=ecf49e5173d, topicName=阳性非小细胞肺癌)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=1a19115, createdName=stfoxst, createdTime=Tue Nov 03 15:14:00 CST 2020, time=2020-11-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1569044, encodeId=f2c41569044bf, content=<a href='/topic/show?id=5b9ee7968f5' target=_blank style='color:#2F92EE;'>#细胞生长#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=77968, encryptionId=5b9ee7968f5, topicName=细胞生长)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=75d615484024, createdName=wwzzly, createdTime=Sun Dec 22 03:14:00 CST 2019, time=2019-12-22, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1039172, encodeId=022210391e2df, content=机制研究离临床仍然有距离，不过与临床结合思考，仍然有帮助的，不能仅仅是纯临床思维，转化思维同样重要, beContent=null, objectType=article, channel=null, level=null, likeNumber=47, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=肿肿, createdTime=Fri Dec 20 15:14:00 CST 2019, time=2019-12-20, status=1, ipAttribution=)]
    2019-12-22 wwzzly

    #细胞生长#

    0

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    2019-12-20 肿肿

    机制研究离临床仍然有距离，不过与临床结合思考，仍然有帮助的，不能仅仅是纯临床思维，转化思维同样重要

    0

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