# Targeting the HGF-MET-TWIST1 pathway to overcome EGFR TKI resistance

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $357,994

## Abstract

Epidermal Growth Factor Receptor (EGFR) mutant (mt) non-small cell lung cancer (NSCLC),
initially has a high response rate to EGFR tyrosine kinase inhibitors (TKIs), however, resistance is inevitable.
HGF-MET pathway activation and an epithelial-mesenchymal transition (EMT) transcription factor (TF) induced
mesenchymal phenotype are commonly observed mechanisms of EGFR TKI resistance. We have identified the
hepatocyte growth factor (HGF)-MET-TWIST1 axis as a novel targetable signaling axis that may account for
both de novo and acquired resistance to EGFR TKIs including osimertinib. Our published data showed that the
EMT-TF, TWIST1 is required for EGFR mt tumorigenesis and can mediated EGFR TKI resistance in vitro and in
vivo through suppression of apoptosis. Targeting TWIST1, genetically or pharmacologically with our first-in-class
TWIST1 inhibitor, harmine resensitized EGFR mt NSCLC to EGFR TKIs. Our preliminary data demonstrate that
HGF increases TWIST1 expression and that TWIST inhibition can reverse HGF-MET mediated EGFR TKI
resistance in vitro. Therefore, TWIST1 maybe the critical targetable node that connects these pathways.
Central hypothesis: HGF-MET mediated induction of TWIST1 leads to the suppression of apoptosis and EGFR
TKI resistance in EGFR mt NSCLC, which can be overcome with TWIST1 inhibition. We will test this hypothesis
in the following Specific Aims:
Aim 1: Determine the mechanism and clinical significance of HGF-dependent TWIST1 induction in EGFR
mutant NSCLC. Hypothesis: HGF leads to increased TWIST1 expression and activity through phosphorylation
by ERK and/or AKT (Aim 1a). We further hypothesize that HGF-MET activation correlates with increased
TWIST1 expression and poor response to EGFR TKIs in the EGFR TKI de novo and acquired resistance setting
in patients (Aim 1b)
Aim 2: Elucidate the mechanism of HGF-TWIST1-mediated EGFR TKI resistance. Hypothesis: TWIST1
mediates HGF-MET dependent EGFR TKI resistance in both de novo and acquired resistance through
suppression of apoptosis in vitro (aim 2a) and in vivo (aim 2b-c).
Aim 3: Evaluate the efficacy of the TWIST1 inhibitor, harmine to overcome HGF-MET induced EGFR TKI
resistance. Hypothesis: Targeting TWIST1 with harmine in combination with osimertinib will overcome HGF-
induced resistance as well as MET driven resistance in the acquired resistance setting in vitro and in vivo.
Translational Impact: There are no FDA approved targeted therapies after progression on osimertinib. We
are uniquely positioned to identify TWIST1 as a mediator of HGF-MET-dependent EGFR TKI resistance and a
novel therapeutic target for the treatment of EGFR TKI resistance.

## Key facts

- **NIH application ID:** 10047773
- **Project number:** 1R01CA244270-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Timothy F. Burns
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,994
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047773

## Citation

> US National Institutes of Health, RePORTER application 10047773, Targeting the HGF-MET-TWIST1 pathway to overcome EGFR TKI resistance (1R01CA244270-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10047773. Licensed CC0.

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