The Role of Protocadherin 7 in Lung Adenocarcinoma

Lung cancer is the leading cause of cancer-associated deaths worldwide. Despite recent advances in the development of targeted therapies for lung cancer, most patients develop resistance to these targeted therapies. Our lab has uncovered a key oncogenic role for Protocadherin 7 (PCDH7) in non-small cell lung cancer (NSCLC) (Zhou et al. Cancer Research, 2017; Zhou et al. Molecular Cancer Research, 2019). PCDH7 is frequently overexpressed in human lung cancers, significantly correlating with poor clinical outcome of lung adenocarcinoma patients. PCDH7 knockout in established lung tumor xenografts led to a significant decrease in phospho-EGFR, leading us to hypothesize that PCDH7 may directly interact with EGFR and modulate signaling through this receptor. We demonstrate that PCDH7 interacts with EGFR in a phospho-dependent manner, and that loss of this interaction in PCDH7 truncation mutants reduces EGFR activity and downstream signaling. PCDH7 knockout cells also exhibit decreased EGFR dimerization, suggesting a model whereby PCDH7 promotes EGFR dimerization to stimulate downstream MAPK activation. We also investigated the consequences of PCDH7 loss of function in EGFR mutant human cells and mouse models. Knockout of PCDH7 sensitizes EGFR mutant cell lines to tyrosine kinase inhibitors (TKIs), the current method of treatment for EGFR mutant lung cancers. Furthermore, loss of PCDH7 in EGFR mutant xenografts and genetically engineered mice reduces overall tumor burden. Overall, these findings reveal a new mechanism through which PCDH7 potentiates the MAPK pathway and provide strong rationale for the development of PCDH7-targeting molecules including monoclonal antibodies.

Author dc:creator

• Smith, Bethany Kristina

Contributors dc:contributor

• Conacci-Sorrell, Maralice
• McFadden, David G.
• Zhu, Hao
• O'Donnell, Kathryn A.

• Lung Neoplasms
• Proto-Oncogene Proteins p21(ras)
• Adenocarcinoma of Lung
• Protocadherins

Language dc:language

en

Identifier

1482732356

OAI identifier oai:identifier

oai:tdl-ir.tdl.org:2152.5/10458