The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death.
The ALK inhibitors, alectinib and ceritinib, induce ALK-independent and STAT3-dependent glioblastoma cell death.
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ALK抑制剂alectinib和ceritinib可诱导ALK非依赖性和stat3依赖性胶质母细胞瘤细胞死亡。
DOI：
10.1111/cas.14885
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发表时间：
2021-06
期刊：
影响因子：
5.7
通讯作者：
Tomiyama A
中科院分区：
文献类型：
--
作者：
Kawauchi D;Takahashi M;Satomi K;Yamamuro S;Kobayashi T;Uchida E;Honda-Kitahara M;Narita Y;Iwadate Y;Ichimura K;Tomiyama A
胶质母细胞瘤（GBM）是最常见但极其恶性的脑肿瘤；因此，开发新的GBMs治疗策略势在必行。许多酪氨酸激酶抑制剂（TKIs）已被批准用于各种癌症，但没有一个显示出对GBM的临床疗效。间变性淋巴瘤激酶（ALK）是一种受体酪氨酸激酶（RTK），仅在人类胚胎发育期间被证实。此外，已知各种ALK基因改变在各种肿瘤中作为强大的致癌基因和治疗靶点。不同TKIs对三种表达ALK水平较低的人GBM细胞系（U87MG、LN229和GSC23）的抗肿瘤活性进行了测试；第二代ALK抑制剂alectinib和ceritinib可有效诱导GBM细胞死亡。此外，在人GBM细胞中，alectinib或ceritinib通过抑制信号转导和转录3激活因子，调节RTK信号下游各种分子的激活，诱导caspase依赖性/非依赖性细胞死亡。此外，alectinib和ceritinib对获得性替莫唑胺耐药的U87MG细胞株也显示出抗肿瘤活性。最后，与对照组相比，口服alectinib和ceritinib可延长脑内GBM异种移植小鼠的存活时间。这些结果表明，第二代ALK抑制剂alectinib和ceritinib可能是一种有效的治疗GBM的策略。间变性淋巴瘤激酶（ALK）抑制剂alectinib和ceritinib对体外和体内表达ALK水平极低的胶质母细胞瘤（GBM）细胞显示出抗肿瘤活性。阿勒替尼或塞瑞替尼主要通过抑制GBM细胞的信号转导和转录3激活因子来诱导细胞死亡。Alectinib和ceritinib可能作为治疗GBM的有效药物。
Glioblastoma (GBM) is the most common, but extremely malignant, brain tumor; thus, the development of novel therapeutic strategies for GBMs is imperative. Many tyrosine kinase inhibitors (TKIs) have been approved for various cancers, yet none has demonstrated clinical benefit against GBM. Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that is confirmed only during the embryonic development period in humans. In addition, various ALK gene alterations are known to act as powerful oncogenes and therapeutic targets in various tumors. The antitumor activity of various TKIs was tested against three human GBM cell lines (U87MG, LN229, and GSC23), which expressed substantially low ALK levels; second‐generation ALK inhibitors, alectinib and ceritinib, effectively induced GBM cell death. In addition, treatment with either alectinib or ceritinib modulated the activation of various molecules downstream of RTK signaling and induced caspase‐dependent/‐independent cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in human GBM cells. In addition, alectinib and ceritinib also showed antitumor activity against a U87MG cell line with acquired temozolomide resistance. Finally, oral administration of alectinib and ceritinib prolonged the survival of mice harboring intracerebral GBM xenografts compared with controls. These results suggested that treatment with the second‐generation ALK inhibitors, alectinib and ceritinib, might serve as a potent therapeutic strategy against GBM. Anaplastic lymphoma kinase (ALK) inhibitors, alectinib and ceritinib, demonstrated antitumor activity for glioblastoma (GBM) cells which expressed substantially low ALK levels in vitro and in vivo. Treatment with either alectinib or ceritinib induced cell death mainly by inhibiting signal transducer and activator of transcription 3 activation in GBM cells. Alectinib and ceritinib might serve as potent therapeutic agents against GBM.
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影响因子：
28.2
作者：
Friboulet L;Li N;Katayama R;Lee CC;Gainor JF;Crystal AS;Michellys PY;Awad MM;Yanagitani N;Kim S;Pferdekamper AC;Li J;Kasibhatla S;Sun F;Sun X;Hua S;McNamara P;Mahmood S;Lockerman EL;Fujita N;Nishio M;Harris JL;Shaw AT;Engelman JA
通讯作者：
Engelman JA
影响因子：
51.1
作者：
Gadgeel, Shirish M.;Gandhi, Leena;Ou, Sai-Hong Ignatius
通讯作者：
Ou, Sai-Hong Ignatius
影响因子：
4.8
作者：
Fujikawa, K;Kamiya, H;Kasai, H
通讯作者：
Kasai, H
影响因子：
64.8
作者：
Mosse, Yael P.;Laudenslager, Marci;Longo, Luca;Cole, Kristina A.;Wood, Andrew;Attiyeh, Edward F.;Laquaglia, Michael J.;Sennett, Rachel;Lynch, Jill E.;Perri, Patrizia;Laureys, Genevieve;Speleman, Frank;Kim, Cecilia;Hou, Cuiping;Hakonarson, Hakon;Torkamani, Ali;Schork, Nicholas J.;Brodeur, Garrett M.;Tonini, Gian P.;Rappaport, Eric;Devoto, Marcella;Maris, John M.
通讯作者：
Maris, John M.
影响因子：
50.3
作者：
Sakamoto, Hiroshi;Tsukaguchi, Toshiyuki;Aoki, Yuko
通讯作者：
Aoki, Yuko