Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition.
Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition.
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DOI：
10.1186/1476-4598-9-121
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发表时间：
2010-05-26
期刊：
影响因子：
37.3
通讯作者：
Giordano S
中科院分区：
文献类型：
--
作者：
Corso S;Ghiso E;Cepero V;Sierra JR;Migliore C;Bertotti A;Trusolino L;Comoglio PM;Giordano S
胃癌是世界上第二大癌症死亡原因。受体酪氨酸激酶 MET 在许多胃癌中被组成型激活，并且其表达是某些胃癌细胞存活所必需的。因此，MET被认为是针对此类肿瘤进行靶向治疗干预的良好候选者，MET抑制剂最近进入了临床试验。针对酪氨酸激酶的疗法的主要问题之一是许多肿瘤对治疗没有反应或最终对药物产生耐药性。因此，必须进行前瞻性研究来确定可能导致对这些疗法产生耐药性的分子机制。我们的体外和体内结果表明，在 MET 成瘾的胃癌细胞中，HER（人类表皮受体）家族成员的激活会诱导对 MET 沉默或 PHA-665752（一种选择性激酶抑制剂）抑制的抵抗。我们提供的分子证据强调了 EGFR、HER3 以及 MET 和 HER 家族常见的下游信号通路在 MET 抑制剂耐药性中的作用。此外，我们发现体外产生的对 MET 抑制具有抗性的胃癌细胞系表现出 HER 家族成员的过度表达，其激活有助于维持抗性。我们的研究结果预测，具有 HER 家族成员组成型激活的胃癌肿瘤对 MET 抑制反应较差，即使该受体具有组成型活性。此外，这些改变的出现也可能是最初反应性肿瘤出现耐药性的原因。
Gastric cancer is the second leading cause of cancer mortality in the world. The receptor tyrosine kinase MET is constitutively activated in many gastric cancers and its expression is strictly required for survival of some gastric cancer cells. Thus, MET is considered a good candidate for targeted therapeutic intervention in this type of tumor, and MET inhibitors recently entered clinical trials. One of the major problems of therapies targeting tyrosine kinases is that many tumors are not responsive to treatment or eventually develop resistance to the drugs. Perspective studies are thus mandatory to identify the molecular mechanisms that could cause resistance to these therapies. Our in vitro and in vivo results demonstrate that, in MET-addicted gastric cancer cells, the activation of HER (Human Epidermal Receptor) family members induces resistance to MET silencing or inhibition by PHA-665752 (a selective kinase inhibitor). We provide molecular evidences highlighting the role of EGFR, HER3, and downstream signaling pathways common to MET and HER family in resistance to MET inhibitors. Moreover, we show that an in vitro generated gastric cancer cell line resistant to MET-inhibition displays overexpression of HER family members, whose activation contributes to maintenance of resistance. Our findings predict that gastric cancer tumors bearing constitutive activation of HER family members are poorly responsive to MET inhibition, even if this receptor is constitutively active. Moreover, the appearance of these alterations might also be responsible for the onset of resistance in initially responsive tumors.
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影响因子：
8
作者：
Maggiora, P;Marchio, S;Comoglio, PM
通讯作者：
Comoglio, PM
影响因子：
64.8
作者：
GIORDANO, S;PONZETTO, C;COMOGLIO, PM
通讯作者：
COMOGLIO, PM
影响因子：
78.5
作者：
Chabner, BA;Roberts, TG
通讯作者：
Roberts, TG
DOI：
10.1073/pnas.0707270105
发表时间：
2008-01-15
影响因子：
11.1
作者：
Guo, Ailan;Villen, Judit;Comb, Michael J.
通讯作者：
Comb, Michael J.
影响因子：
8
作者：
Corso, S.;Migliore, C.;Giordano, S.
通讯作者：
Giordano, S.