# Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC

> **NIH NIH P50** · EMORY UNIVERSITY · 2022 · $377,671

## Abstract

Summary/Abstract:
Lung cancer is the most common cancer worldwide and the leading cause of cancer-related death in the US.
EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes for patients who have non-small cell lung cancer
(NSCLC) with an activating EGFR mutation (EGFRMT), but many tumors do not respond and most that do will
become resistant in 9-12 months. Osimertinib, a 3rd generation EGFR TKI, has recently advanced to frontline
therapy for EGFRMT NSCLC, irrespective of T790M mutation, but treatment options remain limited for patients
who develop resistant tumors. This proposal describes preclinical studies to evaluate inhibition of the MERTK
receptor tyrosine kinase in combination with EGFR TKIs for treatment of EGFRMT NSCLC and includes a phase
1b clinical trial to test the combination in these patients. 70% of NSCLCs have abnormally high levels of MERTK
and inhibition in tumor cells decreases tumor growth in mice. MERTK is also present in immune cells in the tumor
microenvironment, where it suppresses the anti-tumor innate immune response. Our data suggest that inhibition
of MERTK reprograms the immune system to attack the tumor. MERTK can also mediate resistance to EGFR
TKIs, including osimertinib, suggesting that MERTK inhibition will sensitize EGFRMT tumors to treatment with
EGFR TKIs and may decrease development of resistance. These data identify MERTK as a new target in NSCLC
and implicate MERTK-targeted inhibitors as an unprecedented opportunity to provide a three-pronged
therapeutic approach in a single drug, leading to (1) direct tumor cell killing, (2) activation of anti-tumor innate
immunity, and (3) increased sensitivity to EGFR TKI therapy. To test this idea and generate drugs that can be
used in humans, we developed MERTK-selective TKIs, including MRX-2843. MRX-2843 is effective as
monotherapy in mice and increases sensitivity to EGFR TKIs in EGFRMT NSCLC cells. The proposed studies
use MRX-2843 and other MERTK inhibitors to investigate the effects of combined MERTK and EGFR inhibition
in cell culture and mouse models of EGFRMT NSCLC, including models with tumor cells implanted directly in the
lung, models derived from fresh patient samples, and models of tumor cell metastasis. Mice with mertk knock-
out will also be used to determine the effects of MERTK inhibition in the tumor microenvironment and its impact
on anti-tumor immunity. Additional studies will determine how MERTK inhibition in the immune system leads to
tumor rejection. Finally, a highlight of this project is the dedicated clinical trial of MRX-2843 and osimertinib in
patients with advanced EGFRMT NSCLC, a study that includes 2 expansion cohorts with paired collection of pre-
and post-treatment tumor biopsies and blood samples to evaluate biomarkers of MERTK inhibition, including
changes in immune function, following treatment with MRX-2843. The results from the clinical trial and
associated studies will provide more effective and less toxic treatment op...

## Key facts

- **NIH application ID:** 10459441
- **Project number:** 5P50CA217691-04
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** DOUGLAS K GRAHAM
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $377,671
- **Award type:** 5
- **Project period:** 2019-07-10 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459441

## Citation

> US National Institutes of Health, RePORTER application 10459441, Project 2: Targeting MERTK to improve outcomes for EGFR-mutated NSCLC (5P50CA217691-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459441. Licensed CC0.

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