TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma

Journal of Experimental & Clinical Cancer Research

John W. Barrett¹  Nicole Pinto¹  John Yoo²  Kevin Fung²  Danielle MacNeil²  Joe S. Mymryk³  Kara M. Ruicci⁴  Anthony C. Nichols⁵  Paul Plantinga⁶  Christopher J. Howlett⁶  William Stecho⁶  Paul C. Boutros⁷  Jalna Meens⁸  Laurie Ailles⁹ 

[1] Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, Room B3-431A, 800 Commissioners Road East, N6A 5W9, London, ON, Canada;Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, Room B3-431A, 800 Commissioners Road East, N6A 5W9, London, ON, Canada;Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, Room B3-431A, 800 Commissioners Road East, N6A 5W9, London, ON, Canada;Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;Department of Microbiology and Immunology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, Room B3-431A, 800 Commissioners Road East, N6A 5W9, London, ON, Canada;Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, Room B3-431A, 800 Commissioners Road East, N6A 5W9, London, ON, Canada;Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;Department of Pathology & Laboratory Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada;Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA, USA;Institute for Precision Health, University of California, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, CA, USA;Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada;

关键词: Alpelisib;    BYL719;    PI3-kinase;    PI3K;    Head and neck cancer;    HNSCC;    AXL;    TYRO3;   

DOI  :  10.1186/s13046-020-01713-9

来源: Springer

【 摘 要 】

BackgroundAberrant activation of the phosphatidylinositol 3-kinase (PI3K) pathway is common in many malignancies, including head and neck squamous cell carcinoma (HNSCC). Despite pre-clinical and clinical studies, outcomes from targeting the PI3K pathway have been underwhelming and the development of drug resistance poses a significant barrier to patient treatment. In the present study, we examined mechanisms of acquired resistance to the PI3Kα inhibitor alpelisib (formerly BYL719) in HNSCC cell lines and patient-derived xenografts (PDXs).MethodsFive unique PDX mouse models and three HNSCC cell lines were used. All cell lines and xenografts underwent genomic characterization prior to study. Serial drug treatment was conducted in vitro and in vivo to develop multiple, clinically-significant models of resistance to alpelisib. We then used reverse phase protein arrays (RPPAs) to profile the expression of proteins in parental and drug-resistant models. Top hits were validated by immunoblotting and immunohistochemistry. Flow cytometric analysis and RNA interference studies were then used to interrogate the molecular mechanisms underlying acquired drug resistance.ResultsProlonged treatment with alpelisib led to upregulation of TAM family receptor tyrosine kinases TYRO3 and AXL. Importantly, a significant shift in expression of both TYRO3 and AXL to the cell surface was detected in drug-resistant cells. Targeted knockdown of TYRO3 and AXL effectively re-sensitized resistant cells to PI3Kα inhibition. In vivo, resistance to alpelisib emerged following 20–35 days of treatment in all five PDX models. Elevated TYRO3 expression was detected in drug-resistant PDX tissues. Downstream of TYRO3 and AXL, we identified activation of intracellular MAPK signalling. Inhibition of MAPK signalling also re-sensitized drug-resistant cells to alpelisib.ConclusionsWe have identified TYRO3 and AXL receptors to be key mediators of resistance to alpelisib, both in vitro and in vivo. Our findings suggest that pan-TAM inhibition is a promising avenue for combinatorial or second-line therapy alongside PI3Kα inhibition. These findings advance our understanding of the role TAM receptors play in modulating the response of HNSCC to PI3Kα inhibition and suggest a means to prevent, or at least delay, resistance to PI3Kα inhibition in order to improve outcomes for HNSCC patients.

【 授权许可】

CC BY