Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer.
Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer.
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DOI：
10.1038/s41467-017-00450-6
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发表时间：
2017-09-04
影响因子：
16.6
通讯作者：
Rosell R
中科院分区：
文献类型：
--
作者：
Jacobsen K;Bertran-Alamillo J;Molina MA;Teixidó C;Karachaliou N;Pedersen MH;Castellví J;Garzón M;Codony-Servat C;Codony-Servat J;Giménez-Capitán A;Drozdowskyj A;Viteri S;Larsen MR;Lassen U;Felip E;Bivona TG;Ditzel HJ;Rosell R
具有活化表皮生长因子受体（EGFR）突变的非小细胞肺癌患者通常受益于EGFR酪氨酸激酶抑制剂治疗。然而，几乎所有患者都死于通过不同机制发生的获得性EGFR酪氨酸激酶抑制剂耐药。EGFR酪氨酸激酶抑制剂耐药机制的多样性和不可预测性对开发克服EGFR酪氨酸激酶抑制剂耐药的新治疗提出了挑战。在这里，我们发现Akt激活是获得性EGFR酪氨酸激酶抑制剂耐药的一个会聚特征，跨越一系列不同的、已建立的上游耐药机制。EGFR酪氨酸激酶抑制剂和Akt抑制剂联合治疗在多种EGFR酪氨酸激酶抑制剂耐药的非小细胞肺癌模型中引起细胞凋亡和协同生长抑制此外，在获得性EGFR酪氨酸激酶抑制剂耐药的EGFR突变型非小细胞肺癌患者的大多数临床标本中，磷酸化Akt水平升高。我们的研究结果为临床试验提供了理论依据，这些临床试验在磷酸化Akt水平升高的患者中测试Akt和EGFR抑制剂联合治疗，以治疗EGFR酪氨酸激酶抑制剂耐药机制的异质性。EGFR突变型非小细胞肺癌通常对EGFR酪氨酸激酶抑制剂治疗具有耐药性。在这项研究中，作者表明耐药肿瘤显示出高Akt活化，并且与AKT抑制剂的联合治疗在体外和体内引起协同肿瘤生长抑制。
Non-small-cell lung cancer patients with activating epidermal growth factor receptor (EGFR) mutations typically benefit from EGFR tyrosine kinase inhibitor treatment. However, virtually all patients succumb to acquired EGFR tyrosine kinase inhibitor resistance that occurs via diverse mechanisms. The diversity and unpredictability of EGFR tyrosine kinase inhibitor resistance mechanisms presents a challenge for developing new treatments to overcome EGFR tyrosine kinase inhibitor resistance. Here, we show that Akt activation is a convergent feature of acquired EGFR tyrosine kinase inhibitor resistance, across a spectrum of diverse, established upstream resistance mechanisms. Combined treatment with an EGFR tyrosine kinase inhibitor and Akt inhibitor causes apoptosis and synergistic growth inhibition in multiple EGFR tyrosine kinase inhibitor-resistant non-small-cell lung cancer models. Moreover, phospho-Akt levels are increased in most clinical specimens obtained from EGFR-mutant non-small-cell lung cancer patients with acquired EGFR tyrosine kinase inhibitor resistance. Our findings provide a rationale for clinical trials testing Akt and EGFR inhibitor co-treatment in patients with elevated phospho-Akt levels to therapeutically combat the heterogeneity of EGFR tyrosine kinase inhibitor resistance mechanisms. EGFR-mutant non-small cell lung cancer are often resistant to EGFR tyrosine kinase inhibitor treatment. In this study, the authors show that resistant tumors display high Akt activation and that a combined treatment with AKT inhibitors causes synergistic tumour growth inhibition in vitro and in vivo.
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影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro
影响因子：
28.2
作者：
Cheung HW;Du J;Boehm JS;He F;Weir BA;Wang X;Butaney M;Sequist LV;Luo B;Engelman JA;Root DE;Meyerson M;Golub TR;Jänne PA;Hahn WC
通讯作者：
Hahn WC
影响因子：
4.4
作者：
Koch, Heiner;Busto, M. Estela Del Castillo;Kuster, Bernhard
通讯作者：
Kuster, Bernhard
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B
影响因子：
64.5
作者：
Govindan R;Ding L;Griffith M;Subramanian J;Dees ND;Kanchi KL;Maher CA;Fulton R;Fulton L;Wallis J;Chen K;Walker J;McDonald S;Bose R;Ornitz D;Xiong D;You M;Dooling DJ;Watson M;Mardis ER;Wilson RK
通讯作者：
Wilson RK