# MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunity

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $507,204

## Abstract

MERTK and AXL are members of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases that are
aberrantly expressed in cancer cells where they function to promote cell survival. Both MERTK and AXL mediate
resistance to a variety of cytotoxic chemotherapies and molecularly-targeted agents and have additional roles in
macrophages, natural killer cells, and other innate immune cells where they function to suppress anti-tumor
immunity, leading to enhanced tumor growth and metastasis. These and other data implicate MERTK and AXL
as therapeutic targets in a wide variety of human tumors. Moreover, because of the oncogenic roles for MERTK
and AXL in both tumor and immune cells, inhibitors are expected to provide anti-tumor action mediated by both
direct tumor cell killing and modulation of the innate immune response. Numerous small molecule inhibitors and
antibodies targeting AXL or MERTK are in development, including several tyrosine kinase inhibitors (TKIs) that
are currently in clinical trials.
Despite robust initial responses, clinical efficacy of TKIs that target a single oncogenic driver has historically
been limited by development of resistance as a result of acquired mutations or activation of compensatory bypass
signaling. Closely-related proteins that share common downstream signaling pathways can often provide bypass
signaling and thereby mediate resistance. Indeed, MERTK mediates resistance to AXL inhibitors and vice versa,
suggesting that at least in some cases, dual inhibition of MERTK and AXL may be a more effective therapeutic
strategy than MERTK or AXL inhibition alone. Consistent with this hypothesis, MERTK and AXL inhibitors
mediate synergistic anti-tumor activity in a variety of epithelial cancers. Thus, the overlapping roles for MERTK
and AXL in tumor and immune cells, their roles in resistance to a variety of therapies, and their dual roles in
tumor cells and the innate immune system support development of agents that target both MERTK and AXL. To
date, INCB081776 is the only dual MERTK/AXL TKI described; however, the structure and selectivity of the
compound have not been publicly disclosed.
We have previously developed and optimized MERTK-selective TKIs. We hypothesize that in some cases a dual
MERTK and AXL inhibitor will be more effective for treatment of NSCLC and other cancers than agents targeting
MERTK or AXL alone. Here, we propose to utilize a novel computational methodology in combination with
enzymatic, cell-based and pharmacodynamic assays to develop novel, potent, and selective dual MERTK and
AXL inhibitors and validate their biochemical and functional activities in MERTK and AXL-dependent
subcutaneous and orthotopic NSCLC xenograft models and immune-competent syngeneic NSCLC models. At
the completion of this work, we expect to deliver a dual MERTK/AXL-selective inhibitor suitable for advancement
to GLP toxicity studies in multiple species, all of the preclinical validation studies to support an IND application
...

## Key facts

- **NIH application ID:** 10134287
- **Project number:** 5R01CA249190-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** DOUGLAS K GRAHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $507,204
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134287

## Citation

> US National Institutes of Health, RePORTER application 10134287, MERTK/AXL dual inhibitors provide novel treatment for cancer by targeting tumor cells and activating anti-tumor immunity (5R01CA249190-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134287. Licensed CC0.

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