According to the most prevalent, poor prognosis, and lowest 5 year survival rate, patients with non-small cell lung cancer (NSCLC) are one of the most common issues in global health problem. Although tyrosine receptor inhibitors (TKI), cetuximab, erlotinib, and gefitinib, which target epidermal growth factor receptor (EGFR), are only effective in certain subpopulations, TKI resistance is developed after a median of 10 to 14 months via acquisition of second mutation as well as several other mechanisms. Developing therapeutic agent against TKI resistance is of critical and essential. In this study, we demonstrated that the derivatives of 1,2-bis-hydroxy- indolizino[6,7-b]indiole diols, a novel class of DNA crosslinking agent, effectively kill NSCLC cell lines including PC9 (exon 19 deletion), PC9/gefb4 (exon 19 deletion and resistant to gefitinib), CL100 (exon 19 deletion), and CL97 (exon 19 deletion and T790M). Our results also showed that BO-1922, one of derivatives, was almost equally effective in suppression the growth of various H1299 cell lines which ectopically expressed wild type or a variety of mutant EGFR (such as including L858R, exon 19 deletion, L858R/T790M, and exon 19 deletion/T790M, respectively). The selected derivatives, BO-1922 and BO-1978, were shown to induce DNA double-strand crosslink by modified comet assay and modulate the expression of DNA repair proteins. By aid of flow cytometric assay, we found that exposure of PC9 and PC9/gefb4 cells to BO-1922 resulted in accumulation of cells at the G2/M phase, while BO-1978 causes cell cycle delay at the G1 and S phase. Furthermore, BO-1922 and BO-1978 given at 25 mg/kg significantly suppressed the growth of PC9/gefb4 xenograft tumors. Our present results revealed that BO-1922 and BO-1978 may have potential against NSCLC with EGFR mutations and gefitinib resistance.

Citation Format: Chi-Wei Chen, Satishkumar Tala, Tsann-Long Su, Te-Chang Lee. Suppression of gefitinib-resistant human lung cancer cells by indolizino[6,7-b]indole derivatives. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4474. doi:10.1158/1538-7445.AM2013-4474