Epidermal Growth Factor Receptor Regulation of Ewing Sarcoma Cell Function

Abstract

Objective: Ewing sarcoma (ES) is a type of childhood cancer probably arising from stem mesenchymal or neural crest cells. The epidermal growth factor receptor (EGFR) acts as a driver oncogene in many types of solid tumors. However, its involvement in ES remains poorly understood. Methods: Human SK-ES-1 and RD-ES ES cells were treated with EGF, the EGFR inhibitor tyrphostin (AG1478), or phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK)/mitogen-activated kinase (MAPK) inhibitors. Cell proliferation survival, cycle, and senescence were analyzed. The protein content of possible targets of EGFR manipulation was measured by Western blot. Results: Cell proliferation and survival were increased by EGF and inhibited by AG1478. The EGFR inhibitor also altered the cell cycle, inducing arrest in G1 and increasing the sub-G1 population, reduced polyploidy and increased the population of senescent cells. In addition, AG1478 reduced the levels of phosphorylated AKT (p-AKT), ERK, p-ERK, cyclin D1, and brain-derived neurotrophic factor (BDNF), while enhancing p53 levels. Cell proliferation was also impaired by inhibitors of PI3K or ERK, alone or combined with AG1478. Conclusions: Our findings reveal novel aspects of EGFR regulation of ES cells and provide early evidence for antitumor activities of EGFR inhibitors in ES.

TAE226, a dual inhibitor of focal adhesion kinase and insulin‐like growth factor‐I receptor, is effective for Ewing sarcoma

“…40 Herein, we also found that combined TAE226 and conventional chemotherapeutic (vincristine, doxorubicin, and etoposide) treatment had synergistic effects against EWS. Recently, other candidate EWS inhibitors, such as EGFR and Trk inhibitors, 43,44 have been reported to be potential future therapeutic agents. A combination therapy of these drugs in addition to conventional chemotherapy and TAE226 treatment may improve the prognosis of patients with EWS.…”

Ewing Sarcoma Meets Epigenetics, Immunology and Nanomedicine: Moving Forward into Novel Therapeutic Strategies

“…Consistently, B7-H3-based CARs are now in phase I clinical trials in pediatric solid tumors including EWS (NCT04897321, NCT04483778). Finally, the epithelial growth factor receptor (EGFR) is another target for CAR therapy in EWS and its inhibition has an antitumor activity in vitro [ 101 ]. A phase I trial using EGFR-CAR (EGFR806) is recruiting relapsed patients with preliminary data indicating acceptable toxicity and antitumor activity in children and young adults (NCT03618381) [ 102 ].…”

Antibody Conjugates for Sarcoma Therapy: How Far along Are We?

“…It is involved in routine cellular processes such as proliferation, differentiation, and cellular development [83]. EGFR is highly expressed in several solid cancers [84]. EGFR is overexpressed in up to 76% of embryonal RMS cases, so it is considered a suitable target for RMS immunotherapy [85].…”