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

Kourtney L Kostecki; Mari Iida; Anne L Wiley; Stanley Kimani; Bridget Mehall; Kaitlin Tetreault; Roxana Alexandridis; Menggang Yu; Seungpyo Hong; Ravi Salgia; Justine Y Bruce; Raymond B Birge; Paul M Harari; Deric L Wheeler

doi:10.1002/hed.27340

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

Head Neck. 2023 May;45(5):1255-1271. doi: 10.1002/hed.27340. Epub 2023 Mar 20.

Authors

Kourtney L Kostecki¹, Mari Iida¹, Anne L Wiley¹, Stanley Kimani², Bridget Mehall¹, Kaitlin Tetreault³, Roxana Alexandridis³, Menggang Yu³, Seungpyo Hong^{4

5

6}, Ravi Salgia⁷, Justine Y Bruce^{6

8}, Raymond B Birge², Paul M Harari^{1

6}, Deric L Wheeler^{1

6}

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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Head and Neck Neoplasms*
Mice
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins*
Tumor Microenvironment
c-Mer Tyrosine Kinase

Substances

atezolizumab
c-Mer Tyrosine Kinase
Mertk protein, mouse
Protein Kinase Inhibitors
Proto-Oncogene Proteins
AXL receptor tyrosine kinase, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding