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CLIN CANCER RES：靶向AXL和mTOR通路可以克服小细胞肺癌原发或获得性WEE1抑制剂耐药

2017-10-29 MedSci MedSci原创

小细胞肺癌AXLmTORWEE1
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靶向DNA修复和细胞周期检查点的药物是小细胞肺癌的有效治疗手段。在这些药物中，WEE1抑制剂AZD1775在某些小细胞肺癌患者中有抗肿瘤活性，但是耐药依然常见。了解原发及获得性耐药机制对开发出有效的WEE1抑制剂联合疗法至关重要。CLIN CANCER RES近期发表了一篇文章，研究其耐药机制。

靶向DNA修复和细胞周期检查点的药物是小细胞肺癌的有效治疗手段。在这些药物中，WEE1抑制剂AZD1775在某些小细胞肺癌患者中有抗肿瘤活性，但是耐药依然常见。了解原发及获得性耐药机制对开发出有效的WEE1抑制剂联合疗法至关重要。CLIN CANCER RES近期发表了一篇文章，研究其耐药机制。

作者使用蛋白芯片检测200总蛋白或磷酸化蛋白，并与小细胞肺癌细胞系AZD1775敏感性相联系以识别原发性耐药的标志物。建立了AZD1775获得性抵抗模型研究获得性耐药机制。在体外和体内小细胞肺癌模型中使用联合疗法验证其是否可以克服原发和获得性AZD1775耐药。蛋白组学分析表明AZD1775原发耐药的小细胞肺癌模型中AXL和磷酸化S6水平升高，WEE1/AXL或WEE1/mTOR抑制剂联合可以在体外和体内克服耐药效果。AXL通过mTOR激活ERK通路，导致另一种G2-检查点蛋白CHK1活化。AZD1775获得性耐药模型分析表明AXL，pS6和MET上调，额外使用AXL（TP0903）、双相AXL/MET（cabozanitinib）或mTOR抑制剂可以克服耐药。

文章最后认为，AXL通过下游mTOR信号和引起DNA损伤修复通路活化促进WEE1抑制剂耐药。这些发现表明合理的联合治疗可以增强AZD1775临床疗效。

原始出处：
Triparna Sen,Pan Tong,et al.Targeting AXL and mTOR Pathway Overcomes Primary and Acquired Resistance to WEE1 Inhibition in Small-Cell-Lung Cancer.CLIN CANCER RES.October 2017 doi:10.1158/1078-0432.CCR-17-1284

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    2018-09-03 jklm09

    #抑制剂#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=1851560, encodeId=bae31851560ec, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Sep 03 01:29:00 CST 2018, time=2018-09-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2042602, encodeId=ea6e2042602f8, content=<a href='/topic/show?id=999c88014ea' target=_blank style='color:#2F92EE;'>#获得性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88014, encryptionId=999c88014ea, topicName=获得性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d4b7363, createdName=pandamao2010, createdTime=Wed May 09 11:29:00 CST 2018, time=2018-05-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257058, encodeId=e23025e058bf, content=谢谢分享. , beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:50:07 CST 2017, time=2017-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257057, encodeId=c39025e05738, content=继续关注. , beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:50:02 CST 2017, time=2017-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257056, encodeId=1c4925e05690, content=继续学习. , beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:49:59 CST 2017, time=2017-10-29, status=1, ipAttribution=)]
    2018-05-09 pandamao2010

    #获得性#

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=1851560, encodeId=bae31851560ec, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Sep 03 01:29:00 CST 2018, time=2018-09-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2042602, encodeId=ea6e2042602f8, content=<a href='/topic/show?id=999c88014ea' target=_blank style='color:#2F92EE;'>#获得性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88014, encryptionId=999c88014ea, topicName=获得性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d4b7363, createdName=pandamao2010, createdTime=Wed May 09 11:29:00 CST 2018, time=2018-05-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257058, encodeId=e23025e058bf, content=谢谢分享. , beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:50:07 CST 2017, time=2017-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257057, encodeId=c39025e05738, content=继续关注. , beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:50:02 CST 2017, time=2017-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257056, encodeId=1c4925e05690, content=继续学习. , beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:49:59 CST 2017, time=2017-10-29, status=1, ipAttribution=)]
    2017-10-29 doctorJiangchao

    谢谢分享.

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1851560, encodeId=bae31851560ec, content=<a href='/topic/show?id=f0a254918f0' target=_blank style='color:#2F92EE;'>#抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=41, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=54918, encryptionId=f0a254918f0, topicName=抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=44a360, createdName=jklm09, createdTime=Mon Sep 03 01:29:00 CST 2018, time=2018-09-03, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=2042602, encodeId=ea6e2042602f8, content=<a href='/topic/show?id=999c88014ea' target=_blank style='color:#2F92EE;'>#获得性#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=42, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=88014, encryptionId=999c88014ea, topicName=获得性)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=d4b7363, createdName=pandamao2010, createdTime=Wed May 09 11:29:00 CST 2018, time=2018-05-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257058, encodeId=e23025e058bf, content=谢谢分享. , beContent=null, objectType=article, channel=null, level=null, likeNumber=71, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:50:07 CST 2017, time=2017-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257057, encodeId=c39025e05738, content=继续关注. , beContent=null, objectType=article, channel=null, level=null, likeNumber=61, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:50:02 CST 2017, time=2017-10-29, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=257056, encodeId=1c4925e05690, content=继续学习. , beContent=null, objectType=article, channel=null, level=null, likeNumber=69, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/jW482SpianMayicTRbRZ5RzfPkmqRTH5rHib5mcib8Wb3QdXjhfOK1UubQL2lictjJFdFJ6Lc3cnnCOSWqxXZ4Kk6y5GdzDoy764R/0, createdBy=156e1644785, createdName=doctorJiangchao, createdTime=Sun Oct 29 21:49:59 CST 2017, time=2017-10-29, status=1, ipAttribution=)]
    2017-10-29 doctorJiangchao

    继续关注.

    0

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    2017-10-29 doctorJiangchao

    继续学习.

    0

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