AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.
AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.
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DOI：
10.1016/j.ccell.2015.03.010
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发表时间：
2015-04-13
期刊：
影响因子：
50.3
通讯作者：
Baselga J
中科院分区：
文献类型：
--
作者：
Elkabets M;Pazarentzos E;Juric D;Sheng Q;Pelossof RA;Brook S;Benzaken AO;Rodon J;Morse N;Yan JJ;Liu M;Das R;Chen Y;Tam A;Wang H;Liang J;Gurski JM;Kerr DA;Rosell R;Teixidó C;Huang A;Ghossein RA;Rosen N;Bivona TG;Scaltriti M;Baselga J
磷酸肌醇-3-激酶(PI3K)-α抑制剂在PIK3CA突变或扩增的头颈部鳞状癌（SCC）中显示出临床活性。在研究治疗耐药模型时，我们观察到对PI3Kα抑制变得难以抵抗的SCCs细胞维持了哺乳动物雷帕霉素靶蛋白（mTOR）的pi3k非依赖性激活。这种持续的mTOR激活由酪氨酸激酶受体AXL介导。AXL在实验室模型和接受PI3Kα抑制剂BYL719治疗的耐药肿瘤中都过表达。AXL与表皮生长因子受体（EGFR）二聚并磷酸化，导致磷脂酶Cγ (PLCγ)-蛋白激酶C （PKC）的激活，进而激活mTOR。PI3Kα与EGFR、AXL或PKC抑制剂联合治疗可恢复这种耐药性。
Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous carcinoma (SCC) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance we have observed that SCCs cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)- protein kinase C (PKC), which in turn activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance.
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DOI：
10.1038/nrd3871
发表时间：
2012-12
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
通讯作者：
--
影响因子：
17.1
作者：
Elkabets M;Vora S;Juric D;Morse N;Mino-Kenudson M;Muranen T;Tao J;Campos AB;Rodon J;Ibrahim YH;Serra V;Rodrik-Outmezguine V;Hazra S;Singh S;Kim P;Quadt C;Liu M;Huang A;Rosen N;Engelman JA;Scaltriti M;Baselga J
通讯作者：
Baselga J
影响因子：
7.3
作者：
Meyer AS;Miller MA;Gertler FB;Lauffenburger DA
通讯作者：
Lauffenburger DA
影响因子：
28.2
作者：
Lui VW;Hedberg ML;Li H;Vangara BS;Pendleton K;Zeng Y;Lu Y;Zhang Q;Du Y;Gilbert BR;Freilino M;Sauerwein S;Peyser ND;Xiao D;Diergaarde B;Wang L;Chiosea S;Seethala R;Johnson JT;Kim S;Duvvuri U;Ferris RL;Romkes M;Nukui T;Kwok-Shing Ng P;Garraway LA;Hammerman PS;Mills GB;Grandis JR
通讯作者：
Grandis JR
影响因子：
7.3
作者：
Fan QW;Cheng C;Knight ZA;Haas-Kogan D;Stokoe D;James CD;McCormick F;Shokat KM;Weiss WA
通讯作者：
Weiss WA