Page 48 - D. Cancer biology
P. 48
[D. Cancer biology-35]
Gastric cancer cells develop resistance to IGF1R inhibitors,
anti-cancer drug, through Dexras1
Kyu Hye Chun¹˙², Bo Kyung Yoon¹, Na Hee Hwang¹˙², Sungsoon Fang²˙³, Jae-woo Kim¹˙²˙*
¹Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, South Korea, ²Brain
Korea21 Project for Medical Science, Yonsei University, Seoul 120-752, South Korea, ³Severance Biomedical Science
Institute, Yonsei University College of Medicine, Seoul 120-752, South Korea
Dexamethasone-induced Ras-related protein1, called Dexras1, is a protein which regulates Ras signal transduction
pathways. We previously reported that Dexras1 mediates glucocorticoid-associated adipogenesis and diet-induced
obesity through IGF1R-dependent manner. In cancer cells, IGF1R is already known to be important in proliferation,
migration, and invasion. However, IGF1R inhibitor (Linsitinib) was failed to increase the survival of adrenocortical
carcinoma patients in phase III clinical trial. Here, we hypothesized that high level of Dexras1 induces IGF1R
resistance and ablation of Dexras1 is able to increase the sensitivity to Linsitinib. In TCGA and GDSC database,
Dexras1 expression level was correlated with IGF1R expression level and sensitivity to IGF1R inhibitor, which brought
us to proceed to experiments in vitro and in vivo. Surprisingly, in Linsitinib-resistant cancer cell lines, expression
level of Dexras1 was up-regulated. Also, sensitivity of Linsitinib in xenograft mouse model increased dramatically
when using Dexras1 KO cells in vivo.
Collectively, ablation of dexras1 should be considered as a combination therapy with IGF1R inhibiton.
