# Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm

> **NIH NIH R01** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2021 · $343,923

## Abstract

Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a
paradigm
Investigators: Christine M. Lovly, MD, PhD and Jens Meiler, PhD
 The prospective identification and rational therapeutic targeting of tumor genomic alterations has
revolutionized the care of patients with lung cancer and is now the accepted standard of care for patients with
this disease and with other tumor types. With the advent of sophisticated tumor genotyping, the discovery of
novel genetic variants is accelerating. In order to realize the promise of precision medicine, there is an urgent
need to define the actionability of these variants to select targeted inhibitors. The objective of this proposal
is to develop a novel, data-driven paradigm for characterizing genomic Variants of Uncertain
Significance (VUS) and generating actionable hypotheses about their functions. For this purpose, we
propose an innovative `Personalized Structural Biology' approach. The central hypothesis of this paradigm is
that VUS can be best understood by placing the mutation into the context of protein structures and inferring
from the structural consequences of the mutation on function, phenotype, and drug sensitivity.
 By analyzing the tumors of patients with lung cancer, we have identified three EGFR genomic
alterations that have not previously been reported: 1) EGFR exon 18-25 Kinase Domain Duplication, 2) EGFR-
RAD51 fusions, and 3) EGFR transmembrane domain mutations. Importantly, each of these EGFR variants
was reported as a VUS on clinical genotyping reports because there were no data regarding the sensitivity of
the mutated proteins to EGFR inhibitors now used in clinical practice. We sought to study these EGFR VUS in
an effort to understand on a fundamental mechanistic level how they activate the EGF receptor to promote
oncogenesis. We will integrate structural and computational modeling with various biochemical, molecular, cell
based, and in vivo approaches to investigate the functional effects of these three distinct alterations. Through
these studies, we expect to define previously unrecognized mechanisms of oncogenesis in lung cancer defined
by these novel and recurrently detected EGFR variants. Importantly, understanding the structural and
functional consequences of these EGFR variants is expected to provide novel insights into ErbB receptor
biology and reveal new uses for FDA approved agents in lung cancer and many other tumor types which
harbor ErbB (EGFR/HER2/HER3/HER4) alterations. Furthermore, a key deliverable of the proposed studies
is the development of an innovative, integrated in silico pipeline that is applicable to VUS in any type of cancer,
which we will make freely available via RosettaCommons (www.rosettacommons.org). Thereby, the impact of
the proposed research will go beyond that of the three EGFR variants discussed in this proposal. With the
recent FDA approval of NGS-based tumor testing, the problem of VUS will continue to grow...

## Key facts

- **NIH application ID:** 10132261
- **Project number:** 5R01CA227833-03
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Christine M. Lovly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $343,923
- **Award type:** 5
- **Project period:** 2019-04-19 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132261

## Citation

> US National Institutes of Health, RePORTER application 10132261, Mechanistic insights into Variants of Uncertain Significance (VUS) using novel EGFR variants as a paradigm (5R01CA227833-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10132261. Licensed CC0.

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