SMARCB1/INI1 genetic inactivation is responsible for tumorigenic properties of epithelioid sarcoma cell line VAESBJ.

Epithelioid sarcoma (ES) is a rare soft tissue neoplasm that usually arises in the distal extremities of young adults. ES presents a high rate of recurrences and metastases and frequently poses diagnostic dilemmas. We previously reported loss of tumor suppressor SMARCB1 protein expression and SMARCB1 gene deletion in the majority of ES cases. Unfortunately, no appropriate pre-clinical models of such genetic alteration in ES are available. In the present report we identified lack of SMARCB1 protein due to a homozygous deletion of exon 1 and upstream regulatory region in epithelioid sarcoma cell line VAESBJ. Restoration of SMARCB1 expression significantly affected VAESBJ cell proliferation, anchorage-independent growth and cell migration properties, thus supporting the causative role of SMARCB1 loss in ES pathogenesis. We investigated the translational relevance of this genetic background in ES and demonstrated that SMARCB1 ectopic expression significantly augmented VAESBJ sensitivity to gamma irradiation and acted synergistically with Flavopiridol treatment. In VAESBJ, both activated ERBB1/EGFR and HGFR/MET impinged on AKT and ERK phosphorylation. We demonstrated a synergistic effect of combined inhibition of these two receptor tyrosine kinases using selective small molecule inhibitors on cell proliferation. These observations provide definitive support to the role of SMARCB1 inactivation in the pathogenesis of epithelioid sarcoma and disclose novel clues to therapeutic approaches tailored to SMARCB1-negative ES.