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Clin Cancer Res：SHP2抑制剂TNO155通过阻断RTK信号可增强多种靶向药的疗效

2020-10-12 星云 MedSci原创

RTK信号通路SHP2抑制剂TNO155
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RTK信号通路是多种肿瘤的致癌驱动因素，或者经常在靶向治疗(包括RTKi和MAPKi)时被反馈激活。SHP2抑制剂为抑制RTK信号转导提供了一种吸引人的新方法。本研究旨在评估与新型SHP2抑制剂TNO

RTK信号通路是多种肿瘤的致癌驱动因素，或者经常在靶向治疗(包括RTKi和MAPKi)时被反馈激活。SHP2抑制剂为抑制RTK信号转导提供了一种吸引人的新方法。本研究旨在评估与新型SHP2抑制剂TNO155联合使用的疗效和协同机制，以了解其临床进展。

在体内外合适的肿瘤模型中评估TNO155与EGFRi、BRAFi、KRASG12Ci、CDK4/6i或抗PD-1抗体联合使用的疗效，以及对下游信号的影响。

在EGFR突变型肺癌模型中，TNO155与EGFRi（nazartinib）联合使用具有一定疗效，与持续抑制ERK的效果一致。在BRAF V600E突变的结直肠癌模型中，TNO155通过阻断不同RTKs对ERK反馈的激活而与BRAF+MEK抑制剂发挥协同作用。在KRAS G12C突变的癌细胞中，TNO155可有效阻断KRASG12Ci诱导的野生型KRAS或其他RAS亚型的反馈激活，大大提高了疗效。

此外，TNO155和CDK4/6抑制剂瑞博西尼在大量肺癌和结直肠癌患者源性异种移植模型中均展现出了联合效益，包括携带KRAS突变的模型。最后，TNO155能有效抑制CSF1R（CSF1R对免疫抑制肿瘤相关巨噬细胞的成熟至关重要）对RAS的激活，并表现出与抗PD-1抗体的联合活性。

总之，该研究结果表明，TNO155在RTK和MAPK驱动的癌症及其肿瘤微环境中可以有效阻断具有肿瘤促进和免疫抑制效应的RTK信号，为临床评估这些联合方案提供了依据。

原始出处：

Huai-Xiang Hao, et al. Combinations with allosteric SHP2 inhibitor TNO155 to block receptor tyrosine kinase signaling. Clin Cancer Res October 12 2020 DOI:10.1158/1078-0432.CCR-20-2718

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    2021-02-16 jklm09

    #抑制剂#

    0

  2. [GetPortalCommentsPageByObjectIdResponse(id=1852509, encodeId=8d0b18525099b, 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=21, 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=Tue Feb 16 08:15:22 CST 2021, time=2021-02-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1710260, encodeId=178d1e102602c, content=<a href='/topic/show?id=7ac59e67604' target=_blank style='color:#2F92EE;'>#阻断#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97676, encryptionId=7ac59e67604, topicName=阻断)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b5ca31824852, createdName=41514497@qq.com, createdTime=Sun Apr 18 04:15:22 CST 2021, time=2021-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995617, encodeId=c125199561eab, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=28b7142, createdName=liuquan, createdTime=Sat Mar 13 10:15:22 CST 2021, time=2021-03-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1412293, encodeId=f64214122935e, content=<a href='/topic/show?id=611a1626917' target=_blank style='color:#2F92EE;'>#SHP2#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16269, encryptionId=611a1626917, topicName=SHP2)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=66f92855036, createdName=wmr112, createdTime=Wed Oct 14 14:15:22 CST 2020, time=2020-10-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1032681, encodeId=28ad10326810a, content=谢谢梅斯提供这么好的信息，学到很多, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=内科新手, createdTime=Tue Oct 13 02:15:22 CST 2020, time=2020-10-13, status=1, ipAttribution=)]
    2021-04-18 41514497@qq.com

    #阻断#

    0

  3. [GetPortalCommentsPageByObjectIdResponse(id=1852509, encodeId=8d0b18525099b, 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=21, 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=Tue Feb 16 08:15:22 CST 2021, time=2021-02-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1710260, encodeId=178d1e102602c, content=<a href='/topic/show?id=7ac59e67604' target=_blank style='color:#2F92EE;'>#阻断#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97676, encryptionId=7ac59e67604, topicName=阻断)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b5ca31824852, createdName=41514497@qq.com, createdTime=Sun Apr 18 04:15:22 CST 2021, time=2021-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995617, encodeId=c125199561eab, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=28b7142, createdName=liuquan, createdTime=Sat Mar 13 10:15:22 CST 2021, time=2021-03-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1412293, encodeId=f64214122935e, content=<a href='/topic/show?id=611a1626917' target=_blank style='color:#2F92EE;'>#SHP2#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16269, encryptionId=611a1626917, topicName=SHP2)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=66f92855036, createdName=wmr112, createdTime=Wed Oct 14 14:15:22 CST 2020, time=2020-10-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1032681, encodeId=28ad10326810a, content=谢谢梅斯提供这么好的信息，学到很多, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=内科新手, createdTime=Tue Oct 13 02:15:22 CST 2020, time=2020-10-13, status=1, ipAttribution=)]
    2021-03-13 liuquan

    #2抑制剂#

    0

  4. [GetPortalCommentsPageByObjectIdResponse(id=1852509, encodeId=8d0b18525099b, 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=21, 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=Tue Feb 16 08:15:22 CST 2021, time=2021-02-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1710260, encodeId=178d1e102602c, content=<a href='/topic/show?id=7ac59e67604' target=_blank style='color:#2F92EE;'>#阻断#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97676, encryptionId=7ac59e67604, topicName=阻断)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=b5ca31824852, createdName=41514497@qq.com, createdTime=Sun Apr 18 04:15:22 CST 2021, time=2021-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1995617, encodeId=c125199561eab, content=<a href='/topic/show?id=992411149e' target=_blank style='color:#2F92EE;'>#2抑制剂#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=1114, encryptionId=992411149e, topicName=2抑制剂)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=28b7142, createdName=liuquan, createdTime=Sat Mar 13 10:15:22 CST 2021, time=2021-03-13, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1412293, encodeId=f64214122935e, content=<a href='/topic/show?id=611a1626917' target=_blank style='color:#2F92EE;'>#SHP2#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=25, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=16269, encryptionId=611a1626917, topicName=SHP2)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=66f92855036, createdName=wmr112, createdTime=Wed Oct 14 14:15:22 CST 2020, time=2020-10-14, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1032681, encodeId=28ad10326810a, content=谢谢梅斯提供这么好的信息，学到很多, beContent=null, objectType=article, channel=null, level=null, likeNumber=32, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=f0620, createdName=内科新手, createdTime=Tue Oct 13 02:15:22 CST 2020, time=2020-10-13, status=1, ipAttribution=)]
    2020-10-14 wmr112

    #SHP2#

    0

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    2020-10-13 内科新手

    谢谢梅斯提供这么好的信息，学到很多

    0