# Development of a first-in-class mEGFR dimerization inhibitor

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $351,000

## Abstract

Project Summary/Abstract
The KRAS mutation (mtKRAS) occurs in approximately 25% of all human tumors and confers resistance to
EGFR tyrosine kinase inhibitors (TKI). Targeting KRAS mutations with drugs has been challenging. We are
developing DGD-1202 a specific degrader, not an inhibitor, of activated EGFR kinase that exhibits profound
activity against mtKRAS-driven murine tumor models. Our data indicate that degradation of activated EGFR
without affecting mtKRAS levels could be a novel therapy for TKI-resistant mtKRAS-driven tumors. We
hypothesize that in such wtEGFR/mtKRAS tumor types, kinase-independent roles of EGFR are vital for cell
survival. Therefore, degradation of activated EGFR is sufficient to kill cells, including mtKRAS expressing cells.
The overall goal of our study is to confirm the efficacy and mechanism of action of DGD-1202. Accordingly, the
three specific aims of this proposal are as follows. In Aim 1, we will determine the kinase-independent roles
of EGFR protein in mtKRAS-driven tumors. The ablation of EGFR by siRNA or shRNA kills both EGFR-driven
or mtKRAS expressing cells. This indicates that EGFR protein plays an essential role in cell survival, independent
of its kinase functions. We hypothesize that kinase-dead (KD) EGFR protein expression will rescue cell death
induced by EGFR ablation in these cells. In this aim, we will investigate if kinase-dead EGFR can promote cell
survival and rescue DGD-1202 mediated cell death. In Aim 2, we will elucidate the mechanisms by which
DGD-1202 induced EGFR degradation overcomes mtKRAS mediated TKI resistance. EGFR protein plays
important scaffolding functions, and its ablation results in the loss of membrane transporters such as xCT and
SGLT1. Loss of these transporters limits cellular uptake of cystine and glucose, respectively, thus reducing the
synthesis of glutathione peroxidase, a key free radical scavenger. In this aim, we will investigate the effects of
DGD-1202 induced EGFR degradation on xCT and SGLT1 in mtKRAS-driven cancer cells and its effect on the
accumulation of reactive oxygen intermediates. Based on our preliminary data, we hypothesize that DGD-1202
will reduce xCT and SGLT1 protein levels in wtEGFR cells but have minimal effect in KD EGFR expressing cells,
where DGD-1202 does not degrade EGFR. Finally, in Aim 3, we will assess the efficacy of DGD-1202 in a
panel of mtKRAS-driven, EGFR TKI-resistant xenograft, and transgenic mouse models. Our preliminary
data indicate the robust single-agent activity of DGD-1202 in several mtKRAS-driven cancer models. In this aim,
we will determine the dose and exposure-response profiles. We will also determine the effect of DGD-1202
treatment on long-term survival. This approach will target a broad spectrum of patients and offer a therapeutic
option for both treatment-naive and EGFR-TKI resistant mtKRAS-driven tumors.

## Key facts

- **NIH application ID:** 10435117
- **Project number:** 3R01CA248310-03S1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** THEODORE S LAWRENCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $351,000
- **Award type:** 3
- **Project period:** 2020-04-03 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435117

## Citation

> US National Institutes of Health, RePORTER application 10435117, Development of a first-in-class mEGFR dimerization inhibitor (3R01CA248310-03S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10435117. Licensed CC0.

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