Combining EGFR and mTOR Blockade for the Treatment of Epithelioid Sarcoma

Abstract

Purpose Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. EGFR is overexpressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition. Experimental Design EGFR and mTOR expression/activation was examined via tissue microarray (n=27 human ES specimens; IHC) and in human ES cell lines (WB and qRTPCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation and erlotinib (anti-EGFR small molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin, were evaluated using SCID mouse ES xenograft models. Results EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion, and induced cyclin D1, MMP2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all TMA-evaluable ES tissues; 88% of samples had no or reduced PTEN expression. Similarly, both ES cell lines demonstrated enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration. Conclusions EGFR- and mTOR-signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials.

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

“…Concordantly, combined inhibition of ERBB1/ EGFR and HGFR/MET pathways resulted in enhanced and synergic growth suppression. Thus, our observations provide an explanation for the incomplete response of VAESBJ cell line to EGFR inhibition (32).…”

“…Recently, a role for EGFR activation has been proposed in epithelioid sarcoma (32). Although VAESBJ does not carry EGFR mutation, it displayed sustained, EGFR-independent, phospho-AKT activation, and showed limited response to EGFR inhibition (32). We found that the HGFR/MET pathway cooperates with EGFR in sustaining AKT and ERK phosphorylation.…”

“…We here provide evidence that VAESBJ cells display activation of both the receptor tyrosine kinase ERBB1/EGFR and HGFR/MET. Recently, a role for EGFR activation has been proposed in epithelioid sarcoma (32). Although VAESBJ does not carry EGFR mutation, it displayed sustained, EGFR-independent, phospho-AKT activation, and showed limited response to EGFR inhibition (32).…”

STAT3 and HIF1α Signaling Drives Oncogenic Cellular Phenotypes in Malignant Peripheral Nerve Sheath Tumors

“…It is apparent that many genetic alterations found in MPNSTs lead to amplification of signal transduction pathways that enhance either JAK2/STAT3 or mTORC1/STAT3 signaling, where HIF1a lies downstream of both STAT3 and mTORC1 (28). For instance, PTEN loss is known to occur in both MPNSTs and epithelioid sarcomas (38,39) that gives rise to aberrant signaling through PI3K/mTORC1 (see Fig. 8 for signaling diagram).…”

Prognostic Significance of AKT/mTOR and MAPK Pathways and Antitumor Effect of mTOR Inhibitor in NF1-Related and Sporadic Malignant Peripheral Nerve Sheath Tumors

“…The AKT/mTOR and MAPK pathways are known to be activated in some kinds of sarcomas (19)(20)(21)(22)(23), and several articles support that the AKT/mTOR and/or MAPK pathways, as well as their upstream receptor tyrosine kinases, are activated in MPNSTs (1,24,25). At least in patients with NF1, it is conceivable that Ras activation caused by Nf1 gene deficiency may induce the subsequent activation of the AKT/mTOR and Raf/MEK/ERK pathways.…”