PMID- 26041671 OWN - NLM STAT- MEDLINE DCOM- 20160204 LR - 20200502 IS - 1476-4598 (Electronic) IS - 1476-4598 (Linking) VI - 14 DP - 2015 Jun 4 TI - Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer. PG - 113 LID - 10.1186/s12943-015-0392-3 [doi] LID - 113 AB - BACKGROUND: Therapeutic interventions in the insulin-like growth factor receptor (IGF-1R) pathway were expected to provide clinical benefits; however, IGF-1R tyrosine kinase inhibitors (TKIs) have shown limited antitumor efficacy, and the mechanisms conveying resistance to these agents remain elusive. METHODS: The expression and activation of the IGF-1R and Src were assessed via the analysis of a publicly available dataset, as well as immunohistochemistry, Western blotting, RT-PCR, and in vitro kinase assays. The efficacy of IGF-1R TKIs alone or in combination with Src inhibitors was analyzed using MTT assays, colony formation assays, flow cytometric analysis, and xenograft tumor models. RESULTS: The co-activation of IGF-1R and Src was observed in multiple human NSCLC cell lines as well as in a tissue microarray (n = 353). The IGF-1R and Src proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing NSCLC cells, linsitinib treatment initially inactivated the IGF-1R pathway but led a Src-dependent reactivation of downstream effectors. In low-pSrc-expressing NSCLC cells, linsitinib treatment decreased the turnover of the IGF-1R and Src proteins, ultimately amplifying the reciprocal co-activation of IGF-1R and Src. Co-targeting IGF-1R and Src significantly suppressed the proliferation and tumor growth of both high-pSrc-expressing and low-pSrc-expressing NSCLC cells in vitro and in vivo and the growth of patient-derived tissues in vivo. CONCLUSIONS: Reciprocal activation between Src and IGF-1R occurs in NSCLC. Src causes IGF-1R TKI resistance by acting as a key downstream modulator of the cross-talk between multiple membrane receptors. Targeting Src is a clinically applicable strategy to overcome resistance to IGF-1R TKIs. FAU - Min, Hye-Young AU - Min HY AD - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. snoopy77@snu.ac.kr. FAU - Yun, Hye Jeong AU - Yun HJ AD - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. yunhj4476@hanmail.net. FAU - Lee, Ji-Sun AU - Lee JS AD - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. jslee5995@snu.ac.kr. FAU - Lee, Hyo-Jong AU - Lee HJ AD - College of Pharmacy, Inje University, Gimhae, Gyungnam, 621-749, Republic of Korea. hjlee@inje.ac.kr. FAU - Cho, Jaebeom AU - Cho J AD - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. gslife99@gmail.com. FAU - Jang, Hyun-Ji AU - Jang HJ AD - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. violet558@nate.com. FAU - Park, Shin-Hyung AU - Park SH AD - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. psyji043@hanmail.net. FAU - Liu, Diane AU - Liu D AD - Department of Biostatistics, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. dianeliu@mdanderson.org. FAU - Oh, Seung-Hyun AU - Oh SH AD - College of Pharmacy, Gachon University, Incheon, 406-840, Republic of Korea. shoh@gachon.ac.kr. FAU - Lee, J Jack AU - Lee JJ AD - Department of Biostatistics, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. jjlee@mdanderson.org. FAU - Wistuba, Ignacio I AU - Wistuba II AD - Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. iiwistuba@mdanderson.org. AD - Department of Pathology, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. iiwistuba@mdanderson.org. FAU - Lee, Ho-Young AU - Lee HY AD - College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. hylee135@snu.ac.kr. LA - eng GR - R01 CA100816/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20150604 PL - England TA - Mol Cancer JT - Molecular cancer JID - 101147698 RN - 0 (3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol) RN - 0 (Imidazoles) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazines) RN - EC 2.7.10.1 (Receptor, IGF Type 1) RN - EC 2.7.10.2 (src-Family Kinases) SB - IM MH - Animals MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/pathology MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm/drug effects MH - Humans MH - Imidazoles/pharmacology MH - Lung Neoplasms/*drug therapy/pathology MH - Mice MH - Models, Biological MH - *Molecular Targeted Therapy MH - Phosphorylation/drug effects MH - Protein Kinase Inhibitors/pharmacology/therapeutic use MH - Protein Stability/drug effects MH - Pyrazines/pharmacology MH - Receptor, IGF Type 1/*metabolism MH - *Signal Transduction/drug effects MH - src-Family Kinases/*metabolism PMC - PMC4453276 EDAT- 2015/06/05 06:00 MHDA- 2016/02/05 06:00 PMCR- 2015/06/04 CRDT- 2015/06/05 06:00 PHST- 2014/12/18 00:00 [received] PHST- 2015/05/21 00:00 [accepted] PHST- 2015/06/05 06:00 [entrez] PHST- 2015/06/05 06:00 [pubmed] PHST- 2016/02/05 06:00 [medline] PHST- 2015/06/04 00:00 [pmc-release] AID - 10.1186/s12943-015-0392-3 [pii] AID - 392 [pii] AID - 10.1186/s12943-015-0392-3 [doi] PST - epublish SO - Mol Cancer. 2015 Jun 4;14:113. doi: 10.1186/s12943-015-0392-3.