# Project 4:  Role of Receptor Tyrosine Kinase AXL in HNSCC Therapy Resistance

> **NIH NIH P50** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $245,644

## Abstract

PROJECT SUMMARY
The primary objective of this proposal is to examine the receptor tyrosine kinase AXL as a driver of cetuximab
resistance in Head and Neck Cancer (HNC). Cetuximab, a monoclonal antibody targeting the EGFR, is the
only approved molecular targeting agent in the management of HNC. Despite well established benefit, the
majority of patients do not respond to cetuximab, and those who do respond ultimately manifest resistance.
Intrinsic and acquired resistance to cetuximab is a major obstacle to improving treatment outcome in HNSCC.
Further, limited molecular understanding of cetuximab resistance mechanisms reveals a gap in knowledge in
HNC therapy. To identify novel, targetable mechanisms of cetuximab resistance in HNC we employ human
tumors, patient-derived xenografts (PDXs), and several models of intrinsic and acquired resistance. We have
identified that 1) AXL is overexpressed in HNC and is significantly associated with higher pathologic grade,
metastases, and shorter survival, 2) PDXs resistant to cetuximab have high AXL expression compared to
cetuximab-sensitive PDXs, and AXL blockade can re-sensitize resistant tumors, 3) overexpression of AXL in
cetuximab-sensitive HNC lines render them resistant, whereas kinase dead AXL lines retain sensitivity, 4)
therapeutic targeting of AXL can restore sensitivity to cetuximab in the resistant setting and 5) a unique
mechanism of resistance is identified where AXL activates Src Family Kinases (SFKs) leading to sustained
HER3 signaling. In this proposal we hypothesize that AXL plays an important role in HNC pathogenesis
and therapeutic resistance to cetuximab and that AXL mediates resistance by activating the HER3/PI3K/Akt
axis via SFKs. To test this hypothesis, we will determine 1) if AXL mediates cetuximab resistance in HNC via a
unique circuit involving the SFKs and HER3 (2) If targeting AXL in cetuximab-resistant HNC tumors can
increase the efficacy of cetuximab in HNC (3) if AXL serves as a biomarker for cetuximab-resistance in HNC
and 4) if cetuximab-resistant tumors, taken directly from patients, can be sensitized to cetuximab by inhibiting
AXL signaling. To carry out these studies we have assembled a strong team of molecular biologists,
translational physician-scientists, pathologists and biostatisticians. This investigative strategy holds great
promise for translation to the clinic and brings innovation by leveraging new molecular insights to a significant
existing problem in HNC.

## Key facts

- **NIH application ID:** 9988231
- **Project number:** 5P50DE026787-05
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** DERIC L WHEELER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,644
- **Award type:** 5
- **Project period:** 2016-08-02 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988231

## Citation

> US National Institutes of Health, RePORTER application 9988231, Project 4:  Role of Receptor Tyrosine Kinase AXL in HNSCC Therapy Resistance (5P50DE026787-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9988231. Licensed CC0.

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