PROTOCADHERIN 7 Acts through SET and PP2A to Potentiate MAPK Signaling by EGFR and KRAS during Lung Tumorigenesis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-01, Vol.77 (1), p.187-197
• Main Authors: Zhou, Xiaorong, Updegraff, Barrett L, Guo, Yabin, Peyton, Michael, Girard, Luc, Larsen, Jill E, Xie, Xian-Jin, Zhou, Yunyun, Hwang, Tae Hyun, Xie, Yang, Rodriguez-Canales, Jaime, Villalobos, Pamela, Behrens, Carmen, Wistuba, Ignacio I, Minna, John D, O'Donnell, Kathryn A
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Animals; Blotting, Western; Cadherins - metabolism; Cancer; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell surface; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Epidermal growth factor receptors; Heterografts; Histone Chaperones - metabolism; Humans; Immunoprecipitation; K-Ras protein; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Lungs; MAP kinase; MAP Kinase Signaling System - physiology; MEK inhibitors; Membrane proteins; Mice; Mice, Inbred NOD; Non-small cell lung carcinoma; Polymerase Chain Reaction; Proportional Hazards Models; Protein phosphatase; Protein Phosphatase 2 - metabolism; Proteins; Proto-Oncogene Proteins p21(ras) - metabolism; Protocadherin; Receptor, Epidermal Growth Factor - metabolism; Signal Transduction - physiology; Survival Analysis; Tissue Array Analysis; Transcription Factors - metabolism; Tumorigenesis; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-16-1267-t

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Given the efficacy of membrane proteins as therapeutic targets in human malignancies, we examined cell-surface receptors that may act as drivers of lung tumorigenesis. Here, we report that the PROTOCADHERIN PCDH7 is overexpressed frequently in NSCLC tumors where this event is associated with poor clinical outcome. PCDH7 overexpression synergized with EGFR and KRAS to induce MAPK signaling and tumorigenesis. Conversely, PCDH7 depletion suppressed ERK activation, sensitized cells to MEK inhibitors, and reduced tumor growth. PCDH7 potentiated ERK signaling by facilitating interaction of protein phosphatase PP2A with its potent inhibitor, the SET oncoprotein. By establishing an oncogenic role for PCDH7 in lung tumorigenesis, our results provide a rationale to develop novel PCDH7 targeting therapies that act at the cell surface of NSCLC cells to compromise their growth. Cancer Res; 77(1); 187-97. ©2016 AACR.