TY - JOUR
T1 - PROTOCADHERIN 7 acts through SET and PP2A to potentiate MAPK signaling by EGFR and KRAS during lung tumorigenesis
AU - Zhou, Xiaorong
AU - Updegraff, Barrett L.
AU - Guo, Yabin
AU - Peyton, Michael
AU - Girard, Luc
AU - Larsen, Jill E.
AU - Xie, Xian Jin
AU - Zhou, Yunyun
AU - Hwang, Tae Hyun
AU - Xie, Yang
AU - Rodriguez-Canales, Jaime
AU - Villalobos, Pamela
AU - Behrens, Carmen
AU - Wistuba, Ignacio I.
AU - Minna, John D.
AU - O'Donnell, Kathryn A.
N1 - Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-16-1267-T
DO - 10.1158/0008-5472.CAN-16-1267-T
M3 - Article
C2 - 27821484
AN - SCOPUS:85009250525
SN - 0008-5472
VL - 77
SP - 187
EP - 197
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -