Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and is the leading cause of cancer-associated deaths worldwide. Given the limited effectiveness of current treatment regimes, there is a critical need for the development of new and innovative approaches to identify actionable therapeutic targets to treat NSCLC. We identified PROTOCADHERIN 7 (PCDH7) in a transposon mutagenesis screen for genes that promote transformation of human bronchial epithelial cells (HBECs). Indeed, Protocadherin family members represent an emerging class of molecules with important functions in cancer. We found that that PCDH7 is frequently overexpressed in lung cancer and that high expression of PCDH7 protein in human tumors strongly associates with poor survival of NSCLC patients. Our data demonstrate that PCDH7 overexpression potently enhances KRAS- and EGFR-induced MAPK signaling and tumorigenesis. Loss of PCDH7 sensitizes KRAS-mutant NSCLC cells to MEK inhibitors in vitro, and inhibits tumorigenesis in vivo. The overall objectives of this application are to define the oncogenic activity of PCDH7 in NSCLC using mouse models and human cells, evaluate PCDH7 as a therapeutic target, and identify the molecular mechanisms through which this cell surface protein promotes lung tumorigenesis. We propose to elucidate the role of this putative lung cancer driver gene by testing the following central hypothesis: PCDH7 promotes KRAS-and EGFR-driven lung tumorigenesis by forming a SET/PP2A inhibitory complex that potentiates MAPK- ERK signaling.
Three Specific Aims will be pursued in order to test this hypothesis:
In Aim 1, we will characterize the extent to which PCDH7 accelerates mutant KRAS- and EGFR-mediated tumorigenesis using a conditional PCDH7 transgenic mouse model, and inhibit PCDH7 using somatic genome editing in KrasLSL- G12D; Tp53 fl/fl mice.
In Aim 2, we will elucidate the roles of SET and PP2A in PCDH7-induced MAPK signaling and tumorigenesis. Finally, in Aim 3, we will examine the extent to which PCDH7 inhibition enhances sensitivity to clinically approved inhibitors in NSCLC cells in vitro and in autochthonous mouse models.
These aims will take advantage of our expertise, and that of our collaborators, to evaluate PCDH7 as a therapeutic target, and identify the mechanisms through which this cell surface protein promotes lung tumorigenesis. We anticipate that these studies will yield novel insights into the mechanisms of lung cancer pathogenesis and provide new opportunities to pursue this cell surface receptor as a therapeutic target in KRAS- and EGFR- driven lung cancers.
Lung cancer is the leading cause of cancer deaths worldwide and has limited treatment options. This project proposes to define the oncogenic activity of a new potential therapeutic target in lung cancer known as PCDH7 using mouse models and human cells. Elucidating the role of this protein and its downstream signaling pathways may allow the development of PCDH7-targeted therapies for this devastating malignancy.
|O'Donnell, Kathryn A (2018) Advances in functional genetic screening with transposons and CRISPR/Cas9 to illuminate cancer biology. Curr Opin Genet Dev 49:85-94|
|Zhou, Xiaorong; Padanad, Mahesh S; Evers, Bret M et al. (2018) Modulation of Mutant KrasG12D -Driven Lung Tumorigenesis In Vivo by Gain or Loss of PCDH7 Function. Mol Cancer Res :|