# Admin Supplement - Pathogenesis of Cancer - Role of EGF Receptor Endocytos

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $35,265

## Abstract

Abstract of Parental RO1 CA089151 Grant
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:** 10621504
- **Project number:** 3R01CA089151-19S1
- **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:** $35,265
- **Award type:** 3
- **Project period:** 2022-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10621504

## Citation

> US National Institutes of Health, RePORTER application 10621504, Admin Supplement - Pathogenesis of Cancer - Role of EGF Receptor Endocytos (3R01CA089151-19S1). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/10621504. Licensed CC0.

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