EGF receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors

Kenneth 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

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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 non-seminoma 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.

Original languageEnglish (US)
Pages (from-to)1079-1089
Number of pages11
JournalMolecular Cancer Therapeutics
Volume17
Issue number5
DOIs
StatePublished - May 1 2018

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Epidermal Growth Factor Receptor
Germ Cell and Embryonal Neoplasms
Seminoma
Therapeutics
Embryonal Carcinoma
Endodermal Sinus Tumor
Choriocarcinoma
Fibroblast Growth Factor 2
Sirolimus
Epidermal Growth Factor
Cisplatin
mechanistic target of rapamycin complex 1
Nonseminomatous germ cell tumor
Cell Differentiation
Young Adult
Cell Proliferation
Ligands
Growth
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Chen, K., Fustino, N. J., Shukla, A. A., Stroup, E. K., Budhipramono, A., Ateek, C., ... Amatruda, J. F. (2018). EGF receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors. Molecular Cancer Therapeutics, 17(5), 1079-1089. https://doi.org/10.1158/1535-7163.MCT-17-0137

EGF receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors. / Chen, Kenneth; Fustino, Nicholas J.; Shukla, Abhay A.; Stroup, Emily K.; Budhipramono, Albert; Ateek, Christina; Stuart, Sarai H.; Yamaguchi, Kiyoshi; Kapur, Payal; Frazier, A. Lindsay; Lum, Lawrence; Looijenga, Leendert H.J.; Laetsch, Theodore W; Rakheja, Dinesh; Amatruda, James F.

In: Molecular Cancer Therapeutics, Vol. 17, No. 5, 01.05.2018, p. 1079-1089.

Research output: Contribution to journalArticle

Chen, K, Fustino, NJ, Shukla, AA, Stroup, EK, Budhipramono, A, Ateek, C, Stuart, SH, Yamaguchi, K, Kapur, P, Frazier, AL, Lum, L, Looijenga, LHJ, Laetsch, TW, Rakheja, D & Amatruda, JF 2018, 'EGF receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors', Molecular Cancer Therapeutics, vol. 17, no. 5, pp. 1079-1089. https://doi.org/10.1158/1535-7163.MCT-17-0137
Chen, Kenneth ; Fustino, Nicholas J. ; Shukla, Abhay A. ; Stroup, Emily K. ; Budhipramono, Albert ; Ateek, Christina ; Stuart, Sarai H. ; Yamaguchi, Kiyoshi ; Kapur, Payal ; Frazier, A. Lindsay ; Lum, Lawrence ; Looijenga, Leendert H.J. ; Laetsch, Theodore W ; Rakheja, Dinesh ; Amatruda, James F. / EGF receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors. In: Molecular Cancer Therapeutics. 2018 ; Vol. 17, No. 5. pp. 1079-1089.
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