EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors.

Autor:	Chen KS; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.; Margaret Gill Center for Cancer and Blood Disorders, Children's Health Medical Center, Dallas, Texas., Fustino NJ; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.; Margaret Gill Center for Cancer and Blood Disorders, Children's Health Medical Center, Dallas, Texas., Shukla AA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas., Stroup EK; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas., Budhipramono A; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas., Ateek C; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas., Stuart SH; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas., Yamaguchi K; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas.; Division of Clinical Genome Research, Institute of Medical Science, University of Tokyo, Tokyo, Japan., Kapur P; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas., Frazier AL; Department of Pediatric Oncology, Children's Hospital Dana-Farber Cancer Care, Boston, Massachusetts., Lum L; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas., Looijenga LHJ; Department of Pathology, Erasmus MC - University Medical Center Rotterdam, Rotterdam, the Netherlands., Laetsch TW; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.; Margaret Gill Center for Cancer and Blood Disorders, Children's Health Medical Center, Dallas, Texas., Rakheja D; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas. dinesh.rakheja@utsouthwestern.edu james.amatruda@utsouthwestern.edu.; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas., Amatruda JF; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas. dinesh.rakheja@utsouthwestern.edu james.amatruda@utsouthwestern.edu.; Margaret Gill Center for Cancer and Blood Disorders, Children's Health Medical Center, Dallas, Texas.; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2018 May; Vol. 17 (5), pp. 1079-1089. Date of Electronic Publication: 2018 Feb 26.
DOI:	10.1158/1535-7163.MCT-17-0137
Abstrakt:	Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of GCT exhibit distinct differentiation states, clinical behavior, and response to treatment; however, the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mTORC1 and MAPK pathways were differentially active in the two classes of GCT. Here we show that nonseminomatous germ cell tumors (NSGCT, including embryonal carcinoma, yolk sac tumor, and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Finally, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways. Mol Cancer Ther; 17(5); 1079-89. ©2018 AACR . (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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