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Mol Cancer. 2015 Jun 4;14:113. doi: 10.1186/s12943-015-0392-3.

Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer.

Author information

1
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. snoopy77@snu.ac.kr.
2
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. yunhj4476@hanmail.net.
3
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. jslee5995@snu.ac.kr.
4
College of Pharmacy, Inje University, Gimhae, Gyungnam, 621-749, Republic of Korea. hjlee@inje.ac.kr.
5
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. gslife99@gmail.com.
6
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. violet558@nate.com.
7
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. psyji043@hanmail.net.
8
Department of Biostatistics, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. dianeliu@mdanderson.org.
9
College of Pharmacy, Gachon University, Incheon, 406-840, Republic of Korea. shoh@gachon.ac.kr.
10
Department of Biostatistics, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. jjlee@mdanderson.org.
11
Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. iiwistuba@mdanderson.org.
12
Department of Pathology, The University of Texas M. D. Anderson Cancer Cener, Houston, TX, USA. iiwistuba@mdanderson.org.
13
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 151-742, Republic of Korea. hylee135@snu.ac.kr.

Abstract

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.

PMID:
26041671
PMCID:
PMC4453276
DOI:
10.1186/s12943-015-0392-3
[Indexed for MEDLINE]
Free PMC Article

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