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

Kenneth S Chen, Nicholas J Fustino, Abhay A Shukla, Emily K Stroup, Albert Budhipramono, Christina Ateek, Sarai H Stuart, Kiyoshi Yamaguchi, Payal Kapur, A Lindsay Frazier, Lawrence Lum, Leendert H J Looijenga, Theodore W Laetsch, Dinesh Rakheja, James F Amatruda

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1079-1089
Number of pages11
JournalMolecular Cancer Therapeutics
Volume17
Issue number5
DOIs
Publication statusPublished - May 2018
Externally publishedYes

Keywords

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols/therapeutic use
  • Cell Line, Tumor
  • ErbB Receptors/antagonists & inhibitors
  • Erlotinib Hydrochloride/administration & dosage
  • Humans
  • Interleukin Receptor Common gamma Subunit/genetics
  • Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Neoplasms, Germ Cell and Embryonal/drug therapy
  • Sirolimus/administration & dosage
  • Testicular Neoplasms/drug therapy
  • Tumor Burden/drug effects
  • Xenograft Model Antitumor Assays

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