SGX-523

SGX523 is a c-Met tyrosine kinase inhibitor that failed in clinical trials because of renal toxicity caused by crystal deposits in renal tubules. SGX523 is metabolized by aldehyde oxidase (AOX) in a species-dependent manner to the considerably less soluble 2-quinolinone-SGX523, which is likely involved in the clinically observed obstructive nephropathy. This study investigated the metabolism and renal toxicity of SGX523 in chimeric mice with humanized livers (humanized-liver mice). The 2-quinolinone-SGX523 formation activity was higher in humanized-liver mouse and human hepatocytes than in mouse hepatocytes. Additionally, this activity in the liver cytosolic fraction from humanized-liver mice was inhibited by the AOX inhibitors raloxifene and hydralazine. After oral SGX523 administration, higher maximum concentrations, larger areas under the plasma concentration versus time curves, and higher urinary concentrations of 2-quinolinone-SGX523 were observed in humanized-liver mice than in non-humanized mice. Serum creatinine and blood urea nitrogen levels were elevated in humanized-liver mice following repeated oral SGX523 administration. The accumulation of amorphous material in the tubules and infiltration of inflammatory cells around tubules were observed in the kidneys of humanized-liver mice after repeated oral SGX523 administration. These findings demonstrate that humanized-liver mice are useful for understanding the metabolism and toxicity of SGX523.

Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non‐small‐cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF‐α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c‐MET‐specific inhibitor SGX‐523 in EBC‐1 cells. Next, we discovered increased autocrine production of EGF and TGF‐α in established acquired resistant H3122/TR and EBC‐1/SR cells. Importantly, overexpression of EGF and TGF‐α in two NSCLC cell lines produced resistance to TAE684 and SGX‐523. Clinically, NSCLC patients with high expression of EGF and TGF‐α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF‐α activated EGFR signaling pathways to survive targeted c‐Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF‐ and TGF‐α‐mediated primary and acquired resistance to TAE684/SGX‐523. Taken together, these results suggested increased autocrine EGF and TGF‐α conferred primary and acquired resistance to ALK/c‐Met kinase inhibitors in NSCLC.