Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC

被引：28

作者：

Volz, Caroline ^{[1
,9
]}

Breid, Sara ^{[1
,9
]}

Selenz, Carolin ^{[1
,9
]}

Zaplatina, Alina ^{[1
,9
]}

Golfmann, Kristina ^{[1
,9
]}

Meder, Lydia ^{[1
,9
]}

Dietlein, Felix ^{[1
,13
,14
]}

Borchmann, Sven ^{[1
,9
,10
,11
]}

Chatterjee, Sampurna ^{[1
]}

Siobal, Maike ^{[1
]}

Schoettle, Jakob ^{[1
,2
]}

Florin, Alexandra ^{[3
]}

Koker, Mirjam ^{[1
,9
]}

Nill, Marieke ^{[1
,9
]}

Ozretic, Luka ^{[12
]}

Uhlenbrock, Niklas ^{[7
]}

Smith, Steven ^{[7
]}

Buettner, Reinhard ^{[3
]}

Miao, Hui ^{[5
,6
]}

Wang, Bingcheng ^{[5
,6
]}

Reinhardt, H. Christian ^{[1
,9
]}

Rauh, Daniel ^{[7
]}

Hallek, Michael ^{[1
]}

Acker-Palmer, Amparo ^{[4
]}

Heukamp, Lukas C. ^{[8
]}

Ullrich, Roland T. ^{[1
,9
]}

机构：

[1] Univ Cologne, Ctr Integrated Oncol Aachen Bonn Cologne Duesseld, Dept Internal Med 1, Cologne, Germany

[2] Univ Cologne, Med Fac, Dept Translat Genom, Cologne, Germany

[3] Univ Hosp, Inst Pathol, Med Sch, Cologne, Germany

[4] Goethe Univ Frankfurt, Inst Cell Biol & Neurosci, Frankfurt, Germany

[5] Case Western Reserve Univ, Sch Med, MetroHlth Med Ctr, Rammelkamp Ctr Res, Cleveland, OH USA

[6] Case Western Reserve Univ, Sch Med, Dept Pharmacol & Oncol, Cleveland, OH USA

[7] TU Dortmund Univ, Fac Chem & Chem Biol, Dortmund, Germany

[8] Inst Hematopathol Hamburg, Hamburg, Germany

[9] Ctr Mol Med, Cologne, Germany

[10] Univ Cologne, Dept Internal Med 1, GHSG, Cologne, Germany

[11] Univ Cologne, Dept Internal Med 1, Else Kroner Forschungskolleg Clonal Evolut Canc, Cologne, Germany

[12] Royal Free Hosp, Dept Cellular Pathol, London NW3 2QG, England

[13] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[14] Broad Inst MIT & Harvard, Canc Program, US Inst Pathol, Cambridge, MA 02142 USA

来源：

CELL REPORTS | 2020年 / 31卷 / 04期

关键词：

ENDOTHELIAL GROWTH-FACTOR; ACQUIRED-RESISTANCE; MAMMALIAN TARGET; GENE-EXPRESSION; EPH RECEPTORS; IN-VIVO; ANGIOGENESIS; THERAPY; CANCER; PROGRESSION;

D O I：

10.1016/j.celrep.2020.107568

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF)-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells, expressed in similar to 20% of non-squamous non-small cell lung cancer (NSCLC) patients, leads to a pro-invasive phenotype. Drug-induced inhibition of tumor VEGFR2 interferes with the formation of the EphA2/VEGFR2 heterocomplex, thereby allowing RSK to interact with Serine 897 of EphA2. Inhibition of RSK decreases phosphorylation of Serine 897 EphA2. Selective genetic modeling of Serine 897 of EphA2 or inhibition of EphA2 abrogates the formation of metastases in vivo upon VEGFR2 inhibition. In summary, these findings demonstrate that VEGFR2-targeted therapy conditions VEGFR2-positive NSCLC to Serine 897 EphA2-dependent aggressive tumor growth and metastasis. These data shed light on the molecular mechanisms explaining the limited efficacy of VEGFR2-targeted anti-angiogenic treatment in lung cancer patients.

引用

页数：18

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