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 language | English (US) |
|---|---|
| Pages (from-to) | 1079-1089 |
| Number of pages | 11 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 17 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
T1 - EGF receptor and mTORC1 are novel therapeutic targets in nonseminomatous germ cell tumors
AU - Chen, Kenneth
AU - Fustino, Nicholas J.
AU - Shukla, Abhay A.
AU - Stroup, Emily K.
AU - Budhipramono, Albert
AU - Ateek, Christina
AU - Stuart, Sarai H.
AU - Yamaguchi, Kiyoshi
AU - Kapur, Payal
AU - Frazier, A. Lindsay
AU - Lum, Lawrence
AU - Looijenga, Leendert H.J.
AU - Laetsch, Theodore W
AU - Rakheja, Dinesh
AU - Amatruda, James F
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047816684&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047816684&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-17-0137
DO - 10.1158/1535-7163.MCT-17-0137
M3 - Article
C2 - 29483210
AN - SCOPUS:85047816684
VL - 17
SP - 1079
EP - 1089
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 5
ER -