In Vitro Investigation Demonstrates IGFR/VEGFR Receptor Cross Talk and Potential of Combined Inhibition in Pediatric Central Nervous System Atypical Teratoid Rhabdoid Tumors

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Author(s): Halah Obaid, Sunand Kannappan, Mehul Gupta, Yibing Ruan, Chunfen Zhang, Pinaki Bose*, Aru Narendran.

Journal Name: Current Cancer Drug Targets

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Atypical teratoid rhabdoid tumor of the central nervous system (CNS ATRT) is a malignancy that commonly affects young children. The biological mechanisms contributing to tumor aggressiveness and resistance to conventional therapies in ATRT are unknown. Previous studies have shown the activity of insulin like growth factor-I receptor (IGF-1R) in ATRT tumor specimens and cell lines. IGF-1R has been shown to cross-talk with other receptor tyrosine kinases (RTKs) in a number of cancer types, leading to enhanced cell proliferation. This study aims to evaluate the role of IGF-1 receptor cross-talk in ATRT biology and the potential for therapeutic targeting. Cell lines derived from CNS ATRT specimens were analyzed for IGF-1 mediated cell proliferation. A comprehensive receptor tyrosine kinase (RTK) screen was conducted that identified VEGFR-2 cross-activation following IGF-1 stimulation. In addition, bioinformatics analysis of publicly available cancer growth inhibition data show a positive correlation between IC50 values of the VEGFR inhibitor Axitinib and IGF-1R expression, thus supporting the critical influence of IGF-1R in modulating response to anti-angiogenic therapies. Overall, our data present a novel experimental framework to evaluate and utilize receptor cross-talk mechanisms to select effective drugs and combinations for future therapeutic trials in ATRT.

Keywords: Crosstalk, ATRT, VEGFR, IGF-1R, Drug Combination

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(E-pub Ahead of Print)
DOI: 10.2174/1568009619666191111153049
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