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Receptor tyrosine kinase gene expression profiling of orbital rhabdomyosarcoma unveils MET as a potential biomarker and therapeutic target

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Abstract

Receptor tyrosine kinases (RTKs) serve as molecular targets for the development of novel personalized therapies in many malignancies. In the present study, expression pattern of receptor tyrosine kinases and its clinical significance in orbital RMS has been explored. Eighteen patients with histopathologically confirmed orbital RMS formed part of this study. Comprehensive q-PCR gene expression profiles of 19 RTKs were generated in the cases and controls. The patients were followed up for 59.53 ± 20.93 years. Clustering and statistical analysis tools were applied to identify the significant combination of RTKs associated with orbital rhabdomyosarcoma patients. mRNA overexpression of RTKs which included MET, AXL, EGFR was seen in 60–80% of cases; EGFR3, IGFR2, FGFR1, RET, PDGFR1, VEGFR2, PDGFR2 in 30–60% of cases; and EGFR4, FGFR3,VEGFR3 and ROS,IGFR1, EGFR1, FGFR2, VEGFR1 in 10–30% of cases. Immunoexpression of MET was seen in 89% of cases. A significant association was seen between MET mRNA and its protein expression. In all the cases MET gene expression was associated with worst overall survival (P = 0.03).There was a significant correlation of MET mRNA expression with RET, ROS, AXL, FGFR1, FGFR3, PDGFR1, IGFR1, VEGFR2, and EGFR3 genes. Association between MET gene and collective expression of RTKs was further evaluated by semi-supervised gene cluster analysis and Principal component analysis, which showed well-separated tumor clusters. MET gene overexpression could be a useful biomarker for identifying high risk orbital rhabdomyosarcoma patients. Well-separated tumor clusters confirmed the association between MET gene and collective expression of RTK genes. Therefore, the therapeutic potential of multi-kinase inhibitors targeting MET and the 9 other significant RTKs needs to be explored.

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Funding

This study was financially supported by research grant from University Grants Commission No. F.15-1/2017/PDFWM-2017-18-MAD-46619(SA-II).

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Authors and Affiliations

  1. Ocular Pathology, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, Room No. 725, New Delhi, 110029, India

    Sheetal Chauhan, Seema Sen & Seema Kashyap

  2. Department of Biochemistry, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Khushboo Irshad

  3. Ophthalmoplasty Services, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

    Neelam Pushker & Rachna Meel

  4. Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India

    Mehar Chand Sharma

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This study was conducted after approval from the Institute Ethics Committee, AIIMS, New Delhi Ref No IEC-45/02.02.2018,RP-02/2018.

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13577_2023_993_MOESM1_ESM.tif

Supplementary file 1: Supplementary Figure1. Kaplan–Meier survival curves to show overall survival in rhabdomyosarcoma cases based on the RTKs gene expression. (TIF 112523 KB)

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Chauhan, S., Sen, S., Irshad, K. et al. Receptor tyrosine kinase gene expression profiling of orbital rhabdomyosarcoma unveils MET as a potential biomarker and therapeutic target. Human Cell 37, 297–309 (2024). https://doi.org/10.1007/s13577-023-00993-5

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