A Meta-analysis of Lung Cancer Gene Expression Identifies <i>PTK7</i> as a Survival Gene in Lung Adenocarcinoma

Ron, Chen; Khatri, Purvesh; Mazur, Paweł K.; Polin, Melanie; Zheng, Yanyan; Vaka, Dedeepya; Hoang, Chuong D.; Shrager, Joseph B.; Xu, Yue; Vicent, Silvestre; Butte, Atul J.; Sweet-Cordero, E. Alejandro

doi:10.1158/0008-5472.can-13-2775

Cited by 138 publications

(120 citation statements)

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“…We and others have shown that knockdown of PTK7 decreases proliferation, survival, wound healing, and invasion of esophageal squamous cell carcinoma cells [20] and reduces cell viability and tumor burden in lung adenocarcinoma [31], demonstrating oncogenic roles for PTK7. In contrast, we also noted a tumor-suppressive role of PTK7, as overexpression of PTK7 decreased cell proliferation, invasion, and migration in lung squamous cell carcinoma [32].…”

Section: Discussionmentioning

confidence: 70%

Biphasic effect of PTK7 on KDR activity in endothelial cells and angiogenesis

Shin

Lee

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Protein tyrosine kinase 7 (PTK7) is a member of the defective receptor protein tyrosine kinase family which lacks catalytic activity. Expression of PTK7 is increased in various cancers but its role in carcinogenesis is not well understood. We previously showed that disruption of PTK7 function suppresses VEGF-induced angiogenic phenotypes in HUVECs and mice. Here, we investigated molecular mechanisms for modulating VEGF-induced physiological effects by PTK7. Treatment with a high concentration of extracellular domain of PTK7 (soluble PTK7; sPTK7) or knockdown of PTK7 inhibited VEGF-induced phosphorylation of kinase insert domain receptor (KDR) but did not inhibit phosphorylation of fms-related tyrosine kinase 1 (FLT-1) in HUVECs. PTK7, more specifically sPTK7, interacted with KDR but not with FLT-1 in HUVECs and HEK293 cells. In vitro binding assay showed that sPTK7 formed oligomers with the extracellular domain of KDR (sKDR) up to an approximately 1:3 molar ratio, and vice versa. sPTK7 at lower molar ratios than sKDR enhanced the binding of VEGF to sKDR. At the same or higher molar ratios, it reduced the binding of VEGF to sKDR. Increasing concentrations of sPTK7 or increasing levels of PTK7 expression first increased and then decreased VEGF-induced KDR phosphorylation, migration, and capillary-like tube formation of HUVECs, as well as in vivo angiogenesis. Taken together, our data demonstrates that PTK7 regulates the activity of KDR biphasically by inducing oligomerization of KDR molecules at lower concentrations and by surrounding KDR molecules at higher concentrations.

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Section: Discussionmentioning

confidence: 70%

Biphasic effect of PTK7 on KDR activity in endothelial cells and angiogenesis

Shin

Lee

2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…AXL is a RTK that promotes OVCA metastasis (56). ACTA2 (alpha smooth muscle actin) drives metastasis and poor prognostis in lung cancer (57). ADRA2A (adrenoreceptor alpha 2A), stimulates proliferation and is associated with MAPK activation (58).…”

Section: Discussionmentioning

confidence: 99%

MAPK Activation Predicts Poor Outcome and the MEK Inhibitor, Selumetinib, Reverses Antiestrogen Resistance in ER-Positive High-Grade Serous Ovarian Cancer

Hew

Miller

El-Ashry

et al. 2016

Clinical Cancer Research

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OBJECTIVE While 67% of high grade serous ovarian cancers (HGSOC) express the estrogen receptor (ER), most fail antiestrogen therapy. Since mitogen-activated protein kinases (MAPK) activation is frequent in ovarian cancer, we investigated if estrogen regulates MAPK and if MEK inhibition (MEKi) reverses anti-estrogen resistance. METHODS Effects of MEKi (selumetinib), anti-estrogen (fulvestrant), or both were assayed in ER+ HGSOC in vitro and in xenografts. Response biomarkers were investigated by gene expression microarray and reverse phase protein array (RPPA). Genes differentially expressed in two independent primary HGSOCs datasets with high vs low pMAPK by RPPA were used to generate a “MAPK-activated gene signature”. Gene signature components reversed by MEKi were then identified. RESULTS High intratumor pMAPK independently predicts decreased survival (HR = 1.7, CI>95% 1.3–2.2, p=0.0009) in 408 TCGA HGSOC. A differentially expressed “MAPK-activated” gene subset was also prognostic. “MAPK-activated genes” in HGSOC differ from those in breast cancer. Combined MEK and ER blockade showed greater anti-tumor effects in xenografts than monotherapy. Gene set enrichment analysis and RPPA showed dual therapy downregulated DNA replication and cell cycle drivers, and upregulated lysosomal gene sets. Selumetinib reversed expression of a subset of “MAPK-activated genes” in vitro and/or in xenografts. Three of these genes were prognostic for poor survival (p=0.000265) and warrant testing as a signature predictive of MEKi response. CONCLUSION High pMAPK is independently prognostic and may underlie antiestrogen failure. Data support further evaluation of fulvestrant and selumetinib in ER+ HGSOC. The MAPK-activated HGSOC signature may help identify MEK inhibitor responsive tumors.

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“…We have repeatedly demonstrated the utility of this approach in identifying novel drug targets, diagnostic and prognostic biomarkers, and repurposing FDA-approved drugs in a broad spectrum of diseases including organ transplant, cancer, sepsis, and bacterial and viral infections (14)(15)(16)(17)(18)(19)(20)(21). Here, we applied our multicohort analytical method to 2 SSc gene expression datasets, obtained from 158 skin biopsies from SSc patients, referred to as the UCSF1 cohort (GSE9285) (11) and the Boston cohort (GSE32413) (10) to identify a 415-gene signature.…”

Section: Introductionmentioning

confidence: 99%