High expression levels of total IGF-1R and sensitivity of NSCLC cells in vitro to an anti-IGF-1R antibody (R1507).
BACKGROUND
The IGF receptor type 1 (IGF-1R) pathway is frequently deregulated in human tumors and has become a target of interest for anti-cancer therapy.


RESULTS
We used a panel of 22 non-small cell lung cancer (NSCLC) cell lines to investigate predictive biomarkers of response to R1507, a fully-humanized anti-IGF-1R monoclonal antibody (Ab; Roche). 5 lines were moderately sensitive (25-50% growth inhibition) to R1507 alone. While levels of phospho-IGF-1R did not correlate with drug sensitivity, 4 out of 5 sensitive lines displayed high levels of total IGF-1R versus 1 out of 17 resistant lines (p = 0.003, Fisher's Exact). Sensitive lines also harbored higher copy numbers of IGF-1R as assessed by independent SNP array analysis. Addition of erlotinib or paclitaxel to R1507 led to further growth inhibition in sensitive but not resistant lines. In one EGFR mutant lung adenocarcinoma cell line (11-18), R1507 and erlotinib co-treatment induced apoptosis, whereas treatment with either drug alone induced only cell cycle arrest. Apoptosis was mediated, in part, by the survival-related AKT pathway. Additionally, immunohistochemical (IHC) staining of total IGF-1R with an anti-total IGF-1R Ab (G11;Ventana) was performed on tissue microarrays (TMAs) containing 270 independent NSCLC tumor samples. Staining intensity was scored on a scale of 0 to 3+. 39.3% of tumors showed medium to high IGF-1R IHC staining (scores of 2+ or 3+, respectively), while 16.7% had scores of 3+.


CONCLUSIONS
In NSCLC cell lines, high levels of total IGF-1R are associated with moderate sensitivity to R1507. These results suggest a possible enrichment strategy for clinical trials with anti-IGF-1R therapy.
Gong
Yixuan
Y
Pao Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
Yao
Evelyn
E
Shen
Ronglai
R
Goel
Aviva
A
Arcila
Maria
M
Teruya-Feldstein
Julie
J
Zakowski
Maureen F
MF
Frankel
Stanley
S
Peifer
Martin
M
Thomas
Roman K
RK
Ladanyi
Marc
M
Pao
William
W
D000906:Antibodies / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000737:chemistry* / Q000276:immunology*
D000906:Antibodies; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1