# Pathogenesis of Cancer - Role of EGF Receptor Endocytosis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $367,279

## Abstract

Receptor tyrosine kinases (RTKs) drive development and progression of many types of cancer. The archetypic
member of the RTK family, epidermal growth factor receptor (EGFR), is overexpressed or mutated in bladder,
brain, intestinal, colon, ovarian, lung and head-and-neck cancer. EGFR has become the major prognostic marker
and therapeutic target in cancer. However, despite the success of EGFR targeted therapy in a subset of cancers
expressing constitutively-active mutants of EGFR, EGFR inhibitors have not been effective in cancers expressing
wild-type EGFR. This is attributable in large part to insufficient mechanistic understanding of the regulation of
oncogenic signaling networks involving EGFR in tumors in vivo. The long-term objective of our research is to
elucidate regulatory mechanisms of EGFR signaling and subsequently contribute to addressing the important
clinical question of how to improve EGFR targeted therapy. We propose to accomplish this goal by defining the
mechanisms by which EGFR signaling is regulated by endocytosis focusing on EGFR overexpressing head-and-
neck squamous cell carcinoma (HNSCC) as the main experimental model.
 Our research aims at testing two broad hypotheses: 1) dysregulation of EGFR endocytosis is critical to
cancer cell growth, survival and motility; and 2) endocytic system can be explored to develop new
predictive/prognostic markers and identify new cancer therapeutic targets. Our studies in cultured cells during
last years established working models of key stages of EGFR endocytic trafficking in vitro. We have also
developed approaches to analyze EGFR activities and endocytosis in vivo in mouse tumor xenografts. Our
analysis of the EGFR-dependent phosphoproteome using time-resolved multiplexed mass-spectrometry
identified new putative signaling pathways initiated by EGFR in endosomes. We are now in a unique position to
1) elucidate the mechanisms of endocytic trafficking of EGFR in vivo in EGFR-dependent tumor models; 2) define
the major signaling pathways involved in growth and motility of cancer cells that are triggered by endosomal
EGFR; 3) decipher the complex effects of dysregulated EGFR endocytic trafficking on tumorigenic processes in
mouse tumor models; and 4) test the hypothesis that slow EGFR endocytosis correlates with the sensitivity of
human HNSCC to the therapeutic EGFR antibody, cetuximab. The proposed studies will untangle the multi-
faceted regulatory mechanisms underlying the impact of dysregulated EGFR endocytic trafficking on signaling
processes in tumor cells in vitro and in vivo, and develop strategies for using the components of the EGFR/RTK
endocytic machinery as prognostic markers and therapeutic targets in cancer.

## Key facts

- **NIH application ID:** 10473836
- **Project number:** 5R01CA089151-20
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** ALEXANDER D SORKIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,279
- **Award type:** 5
- **Project period:** 2001-01-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473836

## Citation

> US National Institutes of Health, RePORTER application 10473836, Pathogenesis of Cancer - Role of EGF Receptor Endocytosis (5R01CA089151-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10473836. Licensed CC0.

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