2. Academic Validation
  3. Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer

Dual Axl/MerTK inhibitor INCB081776 creates a proinflammatory tumor immune microenvironment and enhances anti-PDL1 efficacy in head and neck cancer

  • Head Neck. 2023 Mar 20. doi: 10.1002/hed.27340.
Kourtney L Kostecki 1,  Mari Iida 1,  Anne L Wiley 1,  Stanley Kimani 2,  Bridget Mehall 1,  Kaitlin Tetreault 3,  Roxana Alexandridis 3,  Menggang Yu 3,  Seungpyo Hong 4 5 6,  Ravi Salgia 7,  Justine Y Bruce 6 8,  Raymond B Birge 2,  Paul M Harari 1 6,  Deric L Wheeler 1 6
Affiliations

Affiliations

  • 1 Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 2 Rutgers Biomedical Health and Sciences, Rutgers University, Newark, New Jersey, USA.
  • 3 Department of Biostatistics and Medical Informatics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
  • 4 Pharmaceutical Sciences Division, University of Wisconsin School of Pharmacy, Madison, Wisconsin, USA.
  • 5 Yonsei Frontier Lab and Department of Pharmacy, Yonsei University, Seoul, South Korea.
  • 6 University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.
  • 7 Department of Medical Oncology and Experimental Therapeutics, Comprehensive Cancer Center, City of Hope, Duarte, California, USA.
  • 8 Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
PMID: 36939040 DOI: 10.1002/hed.27340
Abstract

Background: The tyrosine kinase receptors Axl and MerTK are highly overexpressed in head and neck Cancer (HNC) cells, where they are critical drivers of survival, proliferation, metastasis, and therapeutic resistance.

Methods: We investigated the role of Axl and MerTK in creating an immunologically "cold" tumor immune microenvironment (TIME) by targeting both receptors simultaneously with a small molecule inhibitor of Axl and MerTK (INCB081776). Effects of INCB081776 and/or anti-PDL1 on mouse oral Cancer (MOC) cell growth and on the TIME were evaluated.

Results: Targeting Axl and MerTK can reduce M2 and induce M1 macrophage polarization. In vivo, INCB081776 treatment alone or with anti-PDL1 appears to slow MOC tumor growth, increase proinflammatory immune infiltration, and decrease anti-inflammatory immune infiltration.

Conclusions: This data indicates that simultaneous targeting of Axl and MerTK with INCB081776, either alone or in combination with anti-PDL1, slows tumor growth and creates a proinflammatory TIME in mouse models of HNC.

Keywords

Axl; MerTK; PDL1; head and neck cancer; tumor microenvironment.

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