Targeting Integrin β3-Src Pathway May Be Potential Strategy for Overcoming Anti-IGF-1R Antibody Resistance
Clinical trials have shown limited efficacy of anti–insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibodies, with the mechanisms of resistance to IGF-1R monoclonal antibody-based therapy remaining undefined. In preclinical studies reported in the Journal of the National Cancer Institute, Dong Hoon Shin, of The University of Texas MD Anderson Cancer Center and colleagues found that the integrin β3-Src signaling cascade and thus Akt were activated by IGF-1 when IGF-1 binding was inhibited by the anti-IGF-1R monoclonal antibody cixutumumab and that targeting integrin β3 or Src resulted in enhanced antitumor activity of cixutumumab in resistant cell lines and xenografts.
Study Details
In the study, the effects of cixutumumab alone and in combination with Src and integrin β3 inhibitors were evaluated in human head and neck squamous cell carcinoma and non–small cell lung cancer cell lines and in cell line– or patient-derived xenograft tumors in athymic nude mice. Cixutumumab-induced changes in cell signaling and IGF-1 binding to integrin β3 were evaluated by Western or ligand blotting, immunoprecipitation, immunofluorescence, cell adhesion analysis, and enzyme-linked immunosorbent assay.
Effects In Vitro
Inhibition of IGF-1 binding to IGF-1R by cixutumumab resulted in IGF-1 binding to integrin β3, inducing activation of integrin signaling through FAK and Src and subsequent stimulation of EGFR and Akt and resulting in cixutumumab resistance. The kinetics of cixutumumab IGF-1R blockade paralleled IGF-dependent stimulation of proximal and distal effectors of integrin-Src signaling, including EGFR, PI3K/Akt, and FAK in cixutumumab-resistant cells. Integrin β3 and Src antagonism resulted in enhanced antitumor activity of cixutumumab in multiple cixutumumab-resistant cell lines, with disruption of integrin β3 or Src restoring the proapoptotic activities of cixutumumab.
Effects In Vivo
In cell line–derived xenografts, treatment with adenovirus-expressing inhibitory c-Src tyrosine kinase (Ad-CSK) and cixutumumab resulted in a reduction in tumor volume that was significantly greater than the sum of reductions with Ad-CSK and cixutumumab alone. In head and neck squamous cell carcinoma patient–derived xenografts, the combination of liposome-encapsulated integrin β3 siRNA and cixutumumab produced a potent antitumor effect that was significant after the start of treatment and sustained over the course of the study.
At the end of treatment, tumor volume in mice treated with the combination was 134 mm3, significantly smaller than that in mice treated with cixutumumab (1,473 mm3) or integrin β3 siRNA (903 mm3) alone (both P < .001). Treatment with the combination resulted in markedly reduced pSrc levels and increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in the tumors compared with control or single-treatment groups. The combination of cixutumumab and a clinically available Src inhibitor (dasatinib [Sprycel]) also produced efficient regulation of tumor growth, expression of pSrc and pAkt, and TUNEL staining.
The investigators concluded, “Increased Src activation through integrin ανβ3 confers considerable resistance against anti-IGF-1R [monoclonal antibody]–based therapies in [ head and neck squamous cell carcinoma] and [non–small cell lung cancer] cells. Dual targeting of the IGF-1R pathway and collateral integrin β3-Src signaling module may override this resistance.”
Ho-Young Lee, PhD, of Seoul National University, is the corresponding author for the Journal of the National Cancer Institute article.
The study was supported by the National Institutes of Health and the National Research Foundation of Korea University.
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