STAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody

Ji-Sun Lee, Ju-Hee Kang, Hye-Jin Boo, Su-Jung Hwang, Sungyoul Hong, Su-Chan Lee, Young-Jun Park, Tae-Moon Chung, Hyewon Youn, Seung Mi Lee, Byoung Jae Kim, June-Key Chung, Yeonseok Chung, William N. William, Young Kee Shin, Hyo-Jong Lee, Seung-Hyun Oh and Ho-Young Lee ()
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Ji-Sun Lee: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea
Ju-Hee Kang: National Cancer Center, Goyang-si, Gyeonggi-do 410 769, Korea
Hye-Jin Boo: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea
Su-Jung Hwang: College of Pharmacy, Inje University, Gimhae, Gyeongnam 621 749, Korea
Sungyoul Hong: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea
Su-Chan Lee: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea
Young-Jun Park: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea
Tae-Moon Chung: Cancer Imaging Center, Seoul National University Hospital
Hyewon Youn: Cancer Imaging Center, Seoul National University Hospital
Seung Mi Lee: Seoul Metropolitan Government Seoul National University Boramae Medical Center
Byoung Jae Kim: Seoul Metropolitan Government Seoul National University Boramae Medical Center
June-Key Chung: Cancer Imaging Center, Seoul National University Hospital
Yeonseok Chung: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea
William N. William: The University of Texas M.D. Anderson Cancer Center
Young Kee Shin: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea
Hyo-Jong Lee: College of Pharmacy, Inje University, Gimhae, Gyeongnam 621 749, Korea
Seung-Hyun Oh: College of Pharmacy, Gachon University
Ho-Young Lee: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151 742, Korea

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumour microenvironment (TME) to innate resistance, to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R monoclonal antibody that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumour infiltration of stromal cells and metastatic tumour growth, and decreases overall survival of mice. Cixutumumab treatment stimulates STAT3-dependent transcriptional upregulation of IGF-2 in cancer cells and recruitment of macrophages and fibroblasts via paracrine IGF-2/IGF-2R activation, resulting in the stroma-derived CXCL8 production, and thus angiogenic and metastatic environment. Silencing IGF-2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer–stroma communication and vascular endothelial cells’ angiogenic activities. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signalling loop may overcome the adverse consequences of anti-IGF-1R monoclonal antibody-based therapies.

Date: 2015
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DOI: 10.1038/ncomms9499

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