Dissecting novel mechanisms of lung cancer pathogenesis

2015

Kathryn O’Donnell, PhD

UT Southwestern Medical Center

Dallas

Dr. O’Donnell has discovered that lung cancer cells make a protein called PCDH7 that is present on the surface of cancer cells where it may be accessible to therapies. In cooperation with the KRAS protein, the PCDH7 protein relays signals from outside the cell to make cancer cells grow faster. She is studying the function of the PCDH7 protein and developing strategies to reduce its effect on the KRAS pathway.

Research Summary

Lung cancer is the leading cause of cancer deaths worldwide and is caused by mutations in DNA that promote uncontrolled cell growth or inappropriate cell survival. Dr. O’Donnell and her group have developed a powerful method that creates specific mutations in DNA of human cells growing in the laboratory. Mutagenized cells are assayed for the ability to form colonies in soft agar (a hallmark of cancer cells) or implanted into mice and assayed for their ability to form tumors. After isolating DNA from colonies or tumors, they can identify the genes that have been altered, thus revealing their cancer-promoting properties.

They applied this strategy to human lung epithelial cells with the goal of discovering new driver genes that promote lung cancer. Among the genes they identified in this screen was PROTOCADHERIN 7 (PCDH7), which encodes a poorly characterized cell surface protein. PCDH7 is present at higher levels in lung cancer cells compared with normal lung epithelial cells and high PCDH7 levels correlate with poor survival of lung cancer patients. They demonstrated that elevating or reducing PCDH7 levels in human lung cancer cells strongly potentiates or inhibits their tumor-forming ability, respectively.

The goals of this project are to correlate PCDH7 expression with clinical features in human lung tumors, investigate the mechanisms through which PCDH7 promotes lung cancer development, and begin to develop therapeutic strategies to inhibit PCDH7 in lung cancer patients. These studies will provide a clear experimental foundation for the development of individualized treatment based on targeting PCDH7 or its downstream signaling pathway.

Technical Abstract

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated deaths worldwide. Given the limited effectiveness of current treatments, there is a significant need to identify new driver genes that participate in lung cancer pathogenesis. Dr. O’Donnell and her group identified PROTOCADHERIN 7 (PCDH7) in a functional screen for genes that promote transformation of human bronchial epithelial cells (HBECs). This is of interest because PCDH7 encodes a poorly characterized cell surface receptor that is frequently overexpressed in NSCLC and high expression strongly associates with poor survival of NSCLC patients. Moreover, the presence of PCDH7 on the cell surface highlights the potential of this molecule as a novel target for future therapeutics.

They demonstrated that 1) enforced expression of PCDH7 is sufficient to promote transformation of HBECs, 2) PCDH7 cooperates with oncogenic KRAS to promote tumorigenesis, and 3) PCDH7 potently enhances KRAS-mediated activation of the ERK1/2 pathway. They will elucidate the role of this lung cancer driver by testing the following central hypothesis: Overexpression of PCDH7 initiates a signal transduction cascade that potentiates KRAS-induced MAPK-ERK signaling to promote lung tumorigenesis. In Aim 1, they will correlate PCDH7 immunoexpression with clinical features of resected NSCLCs. In Aim 2, they will elucidate the mechanisms through which PCDH7 potentiates MAPK signaling and tumorigenesis. In Aim 3, they will develop and test the therapeutic efficacy of PCDH7 blocking antibodies in patient-derived xenografts.

These experiments will yield insights into the mechanisms of PCDH7-mediated transformation and reveal new opportunities to pursue this cell-surface receptor as a therapeutic target in NSCLC.

Key words

Adenocarcinoma

KRAS

Non-small cell lung cancer (NSCLC)

Targeted therapy

Dissecting novel mechanisms of lung cancer pathogenesis

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