Activation of EPHA2-ROBO1 Heterodimer by SLIT2 Attenuates Non-canonical Signaling and Proliferation in Squamous Cell Carcinomas
Saumya Srivastava,
Ka Ming Pang,
Mari Iida,
Michael S. Nelson,
Jiayi Liu,
Arin Nam,
Jiale Wang,
Isa Mambetsariev,
Raju Pillai,
Atish Mohanty,
Nellie McDaniel,
Amita Behal,
Prakash Kulkarni,
Deric L. Wheeler,
Ravi Salgia
Affiliations
Saumya Srivastava
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
Ka Ming Pang
Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
Mari Iida
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI 53705-2275, USA
Michael S. Nelson
Light Microscopy Core, City of Hope National Medical Center, Duarte, CA, USA
Jiayi Liu
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
Arin Nam
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
Jiale Wang
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
Isa Mambetsariev
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
Raju Pillai
Department of Pathology, City of Hope National Medical Center, Duarte, CA, USA
Atish Mohanty
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
Nellie McDaniel
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI 53705-2275, USA
Amita Behal
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
Prakash Kulkarni
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA
Deric L. Wheeler
Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI 53705-2275, USA; Corresponding author
Ravi Salgia
Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA; Corresponding author
Summary: The tyrosine kinase receptor ephrin receptor A2 (EPHA2) is overexpressed in lung (LSCC) and head and neck (HNSCC) squamous cell carcinomas. Although EPHA2 can inhibit tumorigenesis in a ligand-dependent fashion via phosphorylation of Y588 and Y772, it can promote tumorigenesis in a ligand-independent manner via phosphorylation of S897. Here, we show that EPHA2 and Roundabout Guidance Receptor 1 (ROBO1) interact to form a functional heterodimer. Furthermore, we show that the ROBO1 ligand Slit Guidance Ligand 2 (SLIT2) and ensartinib, an inhibitor of EPHA2, can attenuate growth of HNSCC cells and act synergistically in LSCC cells. Our results suggest that patients with LSCC and HNSCC may be stratified and treated based on their EPHA2 and ROBO1 expression patterns. Although ~73% of patients with LSCC could benefit from SLIT2+ensartinib treatment, ~41% of patients with HNSCC could be treated with either SLIT2 or ensartinib. Thus, EPHA2 and ROBO1 represent potential LSCC and HNSCC theranostics.
