Abstract
Hepatocellular carcinoma (HCC) is highly refractory to current therapeutics used in the clinic. DX-2647, a recombinant human antibody, potently neutralizes the action of insulin-like growth factor-II (IGF-II), a ligand for three cell-surface receptors (IGF-IR, insulin receptor A and B isoforms, and the cation-independent mannose-6-phosphate receptor) which is overexpressed in primary human HCC. DX-2647 impaired the growth of tumor xenografts of the HCC cell line, Hep3B; however, xenografts of the HCC cell line, HepG2, were largely unresponsive to DX-2647 treatment. Analysis of a number of aspects of the IGF signaling axis in both cell lines did not reveal any significant differences between the two. However, while DX-2647 abolished phospho (p)-IGF-IR, p-IR and p-AKT signaling in both cell lines, HepG2 showed high levels of p-STAT3, which was unaffected by DX-2647 treatment and was absent from the Hep3B cell line. The driver of p-STAT3 was found to be a secreted cytokine, and treatment of HepG2 cells with a pan- JAK kinase inhibitor resulted in a loss of p-STAT3. These findings implicate the activation of STAT3 as one pathway that may mediate resistance to IGF-II–targeted therapy in HCC.
| Original language | English |
|---|---|
| Pages (from-to) | 971-978 |
| Number of pages | 8 |
| Journal | Translational Oncology |
| Volume | 11 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 1 Aug 2018 |
Keywords
- IGF-II
- antibody therapy
- resistance
- STAT3
- signalling
- hepatocellular carcinoma
- Bioavailability
Cite this
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Differential Sensitivity of Human Hepatocellular Carcinoma Xenografts to an IGF-II Neutralizing Antibody May Involve Activated STAT3. / Greenall, Sameer A.; Donoghue, Jacqueline; Johns, Terrance G.; Adams, Timothy E.
In: Translational Oncology, Vol. 11, No. 4, 01.08.2018, p. 971-978.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Differential Sensitivity of Human Hepatocellular Carcinoma Xenografts to an IGF-II Neutralizing Antibody May Involve Activated STAT3
AU - Greenall, Sameer A.
AU - Donoghue, Jacqueline
AU - Johns, Terrance G.
AU - Adams, Timothy E.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - Hepatocellular carcinoma (HCC) is highly refractory to current therapeutics used in the clinic. DX-2647, a recombinant human antibody, potently neutralizes the action of insulin-like growth factor-II (IGF-II), a ligand for three cell-surface receptors (IGF-IR, insulin receptor A and B isoforms, and the cation-independent mannose-6-phosphate receptor) which is overexpressed in primary human HCC. DX-2647 impaired the growth of tumor xenografts of the HCC cell line, Hep3B; however, xenografts of the HCC cell line, HepG2, were largely unresponsive to DX-2647 treatment. Analysis of a number of aspects of the IGF signaling axis in both cell lines did not reveal any significant differences between the two. However, while DX-2647 abolished phospho (p)-IGF-IR, p-IR and p-AKT signaling in both cell lines, HepG2 showed high levels of p-STAT3, which was unaffected by DX-2647 treatment and was absent from the Hep3B cell line. The driver of p-STAT3 was found to be a secreted cytokine, and treatment of HepG2 cells with a pan- JAK kinase inhibitor resulted in a loss of p-STAT3. These findings implicate the activation of STAT3 as one pathway that may mediate resistance to IGF-II–targeted therapy in HCC.
AB - Hepatocellular carcinoma (HCC) is highly refractory to current therapeutics used in the clinic. DX-2647, a recombinant human antibody, potently neutralizes the action of insulin-like growth factor-II (IGF-II), a ligand for three cell-surface receptors (IGF-IR, insulin receptor A and B isoforms, and the cation-independent mannose-6-phosphate receptor) which is overexpressed in primary human HCC. DX-2647 impaired the growth of tumor xenografts of the HCC cell line, Hep3B; however, xenografts of the HCC cell line, HepG2, were largely unresponsive to DX-2647 treatment. Analysis of a number of aspects of the IGF signaling axis in both cell lines did not reveal any significant differences between the two. However, while DX-2647 abolished phospho (p)-IGF-IR, p-IR and p-AKT signaling in both cell lines, HepG2 showed high levels of p-STAT3, which was unaffected by DX-2647 treatment and was absent from the Hep3B cell line. The driver of p-STAT3 was found to be a secreted cytokine, and treatment of HepG2 cells with a pan- JAK kinase inhibitor resulted in a loss of p-STAT3. These findings implicate the activation of STAT3 as one pathway that may mediate resistance to IGF-II–targeted therapy in HCC.
KW - IGF-II
KW - antibody therapy
KW - resistance
KW - STAT3
KW - signalling
KW - hepatocellular carcinoma
KW - Bioavailability
UR - http://www.scopus.com/inward/record.url?scp=85048719969&partnerID=8YFLogxK
U2 - 10.1016/j.tranon.2018.05.011
DO - 10.1016/j.tranon.2018.05.011
M3 - Article
VL - 11
SP - 971
EP - 978
JO - Translational Oncology
JF - Translational Oncology
SN - 1936-5233
IS - 4
ER -