聚合Akt激活驱动肺癌获得性EGFR抑制剂耐药性。,Nature Communications

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聚合Akt激活驱动肺癌获得性EGFR抑制剂耐药性。
Nature Communications ( IF 14.7 ) Pub Date : 2017-09-04 , DOI: 10.1038/s41467-017-00450-6
Kirstine Jacobsen , Jordi Bertran-Alamillo , Miguel Angel Molina , Cristina Teixidó , Niki Karachaliou , Martin Haar Pedersen , Josep Castellví , Mónica Garzón , Carles Codony-Servat , Jordi Codony-Servat , Ana Giménez-Capitán , Ana Drozdowskyj , Santiago Viteri , Martin R. Larsen , Ulrik Lassen , Enriqueta Felip , Trever G. Bivona , Henrik J. Ditzel , Rafael Rosell

具有激活表皮生长因子受体（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。但是，实际上，所有患者都通过各种机制屈服于获得性EGFR酪氨酸激酶抑制剂耐药性。EGFR酪氨酸激酶抑制剂耐药机制的多样性和不可预测性为开发克服EGFR酪氨酸激酶抑制剂耐药的新疗法提出了挑战。在这里，我们显示了Akt激活是获得的EGFR酪氨酸激酶抑制剂耐药性的趋同特征，横跨各种已建立的上游耐药机制。在多种抗EGFR酪氨酸激酶抑制剂的非小细胞肺癌模型中，EGFR酪氨酸激酶抑制剂和Akt抑制剂的联合治疗可导致凋亡和协同生长抑制。而且，从具有获得性EGFR酪氨酸激酶抑制剂耐药性的EGFR突变非小细胞肺癌患者获得的大多数临床标本中，磷酸化Akt水平增加。我们的发现为在Akt和EGFR抑制剂水平较高的患者中测试Akt和EGFR抑制剂共同治疗，以治疗性地对抗EGFR酪氨酸激酶抑制剂耐药机制的异质性提供了理论依据。 EGFR酪氨酸激酶抑制剂治疗。在这项研究中，

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Convergent Akt activation drives acquired EGFR inhibitor resistance in lung cancer.

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.

更新日期：2017-09-04

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