# The role of PCDH7 in lung cancer pathogenesis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $424,551

## Abstract

PROJECT SUMMARY
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.

## Key facts

- **NIH application ID:** 10098305
- **Project number:** 5R01CA207763-05
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Kathryn Ann O'Donnell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $424,551
- **Award type:** 5
- **Project period:** 2017-03-09 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098305

## Citation

> US National Institutes of Health, RePORTER application 10098305, The role of PCDH7 in lung cancer pathogenesis (5R01CA207763-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10098305. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*