HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features.
HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features.
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HER3激活有助于ALK重排肺癌中具有间质特征的ALK抑制剂耐受细胞的出现。
DOI：
10.1038/s41698-021-00250-8
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发表时间：
2022-01-18
影响因子：
7.9
通讯作者：
Takayama K
中科院分区：
文献类型：
--
作者：
Tanimura K;Yamada T;Okada K;Nakai K;Horinaka M;Katayama Y;Morimoto K;Ogura Y;Takeda T;Shiotsu S;Ichikawa K;Watanabe S;Morimoto Y;Iwasaku M;Kaneko Y;Uchino J;Taniguchi H;Yoneda K;Matoba S;Sakai T;Uehara H;Yano S;Kusaba T;Katayama R;Takayama K
间变性淋巴瘤激酶-酪氨酸激酶抑制剂(ALK-TKIs)在ALK重排的肺癌患者中显示出显著的疗效，但在这些患者中完全缓解的情况很少见。在这里，我们研究了ALK重排肺癌耐药细胞产生和维持的分子机制。基于细胞的分析表明，通过ZEB1蛋白介导的HER3激活和间充质向上皮的转化，有助于维持细胞的存活，并诱导耐受ALK-TKI的细胞的出现。与ALK-TKIs单独治疗相比，PAN-HER抑制剂afatinib和ALK-TKIs联合治疗可防止肿瘤再生长，导致ALK重排的具有间充质特征的肿瘤被根除。此外，ALK重排肺癌患者治疗前临床标本中波形蛋白的表达与ALK-TKI治疗效果差有关。这些结果表明，HER3的激活在ALK-TKI耐受细胞的产生中起着关键作用。此外，抑制HER3信号联合ALK-TKIs显著改善了ALK重排的间叶性肺癌的治疗结果。
Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have shown dramatic efficacy in patients with ALK-rearranged lung cancer; however, complete response in these patients is rare. Here, we investigated the molecular mechanisms underlying the emergence and maintenance of drug-tolerant cells in ALK-rearranged lung cancer. Cell based-assays demonstrated that HER3 activation and mesenchymal-to-epithelial transition, mediated through ZEB1 proteins, help maintain cell survival and induce the emergence of ALK-TKI-tolerant cells. Compared with ALK-TKIs alone, cotreatment with pan-HER inhibitor afatinib and ALK-TKIs prevented tumor regrowth, leading to the eradication of tumors in ALK-rearranged tumors with mesenchymal features. Moreover, pre-treatment vimentin expression in clinical specimens obtained from patients with ALK-rearranged lung cancer was associated with poor ALK-TKI treatment outcomes. These results demonstrated that HER3 activation plays a pivotal role in the emergence of ALK-TKI-tolerant cells. Furthermore, the inhibition of HER3 signals combined with ALK-TKIs dramatically improves treatment outcomes for ALK-rearranged lung cancer with mesenchymal features.
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影响因子：
158.5
作者：
Peters, Solange;Camidge, D. Ross;Mok, Tony
通讯作者：
Mok, Tony
影响因子：
45.3
作者：
Kim, Dong-Wan;Tiseo, Marcello;Camidge, D. Ross
通讯作者：
Camidge, D. Ross
影响因子：
64.8
作者：
Sergina, Natalia V.;Rausch, Megan;Wang, Donghui;Blair, Jimmy;Hann, Byron;Shokat, Kevan M.;Moasser, Mark M.
通讯作者：
Moasser, Mark M.
影响因子：
64.5
作者：
Sharma SV;Lee DY;Li B;Quinlan MP;Takahashi F;Maheswaran S;McDermott U;Azizian N;Zou L;Fischbach MA;Wong KK;Brandstetter K;Wittner B;Ramaswamy S;Classon M;Settleman J
通讯作者：
Settleman J
DOI：
10.1016/j.neo.2016.02.001
发表时间：
2016-03
期刊：
Neoplasia (New York, N.Y.)
影响因子：
--
作者：
Dong X;Fernandez-Salas E;Li E;Wang S
通讯作者：
Wang S