EGFR and Akt Signaling in Rhabdomyosarcoma Pathogenesis




Granados, Valerie Ann

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Rhabdomyosarcoma is an aggressive soft-tissue malignancy comprised microscopically of neoplastic skeletal muscle-lineage precursors that fail to exit the cell-cycle and fuse into syncytial muscle - the underlying pathogenetic mechanisms for which remain unclear. We previously identified that misregulated myoblast fusion signaling via the TANC1 adaptor molecule promotes neoplastic transformation in RMS cells. As TANC1 is not presently pharmacologically targetable, here we have turned to our Drosophila RMS-related model to identify myoblast fusion-related elements potentially targetable in RMS. Genetic modifier screening against the fly model revealed that decreased Epidermal Growth Factor Receptor (EGFR) activity, which regulates myoblast fusion programming in flies, suppresses PAX-FOXO1 (PF)-induced lethality. As EGFR is pharmacologically targetable, we demonstrate that EGFR inhibitors antagonize RMS in a ERMS-RD cell line, but that other RMS cell lines are resistant. Further interrogation finds that EGFR inhibitor-sensitive cells exhibit marked down-regulated activation of the Akt intracellular signaling transducer, but not MEK/MAPK or STAT3, suggesting that Akt promotes and/or sustains RMS. We then demonstrate that Akt pharmacologic inhibition antagonizes RMS in vitro and in vivo, including RMS cells resistant to EGFR inhibition. We additionally find that sustained Akt1 activity promotes RMS cell terminal differentiation-arrest. Together, these findings point towards Akt activity as a broad RMS underpinning and therapeutic vulnerability.

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