Combinational Therapy Enhances the Effects of Anti-IGF-1R mAb Figitumumab to Target Small Cell Lung Cancer.
BACKGROUND
Small cell lung cancer (SCLC) is a recalcitrant malignancy with distinct biologic properties. Antibody targeting therapy has been actively investigated as a new drug modality.


METHODS
We tested the expression of IGF-1R and calculated the survival in 61 SCLC patients. We also evaluated the anti-tumor effects of anti-IGF-1R monoclonal antibody Figitumumab (CP) on SCLC, and tried two drug combinations to improve CP therapy.


RESULTS
Our clinical data suggested that high IGF-1R expression was correlated with low SCLC patient survival. We then demonstrated the effect of CP was likely through IGF-1R blockage and down-regulation without IGF-1R auto-phosphorylation and PI3K/AKT activation. However, we observed elevated MEK/ERK activation upon CP treatment in SCLC cells, and this MEK/ERK activation was enhanced by ß-arrestin1 knockdown while attenuated by ß-arrestin2 knockdown. We found both MEK/ERK inhibitor and metformin could enhance CP treatment in SCLC cells. We further illustrated the additive effect of metformin was likely through promoting further IGF-1R down-regulation.


CONCLUSIONS
Our results highlighted the potential of anti-IGF-1R therapy and the adjuvant therapy strategy with either MEK/ERK inhibitor or metformin to target SCLC, warranting further studies.
Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.
Hongxin
H
Cao
Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China; Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.
Wei
W
Dong
Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.
Hongchang
H
Shen
Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.
Jun
J
Xu
Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.
Linhai
L
Zhu
Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.
Qi
Q
Liu
Institute of Oncology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China; Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P.R. China.
Jiajun
J
Du
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019390:Arrestins / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000276:immunology* / Q000378:metabolism; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D000071557:beta-Arrestins
D000911:Antibodies, Monoclonal; D019390:Arrestins; D047428:Protein Kinase Inhibitors; D000071557:beta-Arrestins; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; C525021:figitumumab