Abstract 2255: Distinct biological effect of inhibiting the metabolic pathway using active compounds derived from Chinese medicinal herbs in non-small cell lung cancer cells with different EGFR mutational profiles.

Abstract

Abstract Lung cancer is the leading cause of cancer death worldwide. Epidermal Growth Factor Receptor (EGFR) mutation(s) is/are common in non-small cell lung cancer (NSCLC) in Eastern Oriental population, resulting in constitutive activation of EGFR downstream anti-apoptotic signaling and lung tumor formation. Molecular targeted therapy using tyrosine kinase inhibitor (TKI) targeting EGFR shows promising initial response, however, drug resistance and relapse are universal, making the treatment outcome undesirable. Drug resistance could be due to additional EGFR mutation or activation of alternative survival pathways. Therefore, it is important to identify new inhibitors and new molecular targets to tackle TKI-resistance. Chinese Medicinal Herbs (CMHs) has been used to treat variety systemic diseases for many years in China, including diabetes, neurodegenerative disease and cancer. The multi-targeting nature and potential alternation effects on metabolic pathways of CMHs could be a new era for novel cancer drug discovery. Hence, we have reviewed the literature and selected ten single purified compounds derived from CMHs which exhibited the highest potential of cancer suppression effect in NSCLC. We have recruited three EGFR-dependent NSCLC cell lines for drug screening using cytotoxicity assay. A549 is used as EGFR wild-type control. Two TKI-resistant NSCLC cell lines were used, H1975 harbors double mutation (EGFRL858R+T790M) and H1650 harbors EGFRexon 19 deletion with activation of alternative cell survival pathway. H2228 is a NSCLC cell line which harbours EML4-ALK fusion gene and was used as EGFR-independent cell line control. MTT assay revealed that six out of ten candidate agents showed significant cancer-inhibiting effects in H1650, H1975 cells. Three compounds exhibited IC50 value at micro-molar levels while another three compounds exhibited IC50 at as low as nano-molar levels. One compound exhibited specificity on EGFR-dependent NSCLC cell lines, which showed 10-fold more selective than the EGFR-independent H2228 cells. Cell cycle analysis and western blot showed that one effective compound altered the metabolic pathway of glucose metabolism and induced cell cycle arrest at G1 phase in NSCLC with EGFR mutation. However, the anti-proliferative effects were distinct in NSCLC cell lines with different EGFR mutation patterns. Our compound significantly induced cell cycle arrest in four NSCLC in EGFR mutant cell lines but the inhibiting effect was not significant in EGFR wild-type cell line. Immunobloting assay revealed that glycolytic enzymes and cell cycle regulatory gene expression were altered after 72 hr compound treatment in the responsive cells. Further investigation is required to elucidate the underlying reason of drug selectivity and the treatment mechanism of these compounds. Citation Format: Xing Xing Fan, Maria Pik Wong, Zhi Wei Cao, Jian Lin Wu, Hua Zhou, Zhi Hong Jiang, Liang Liu, Elaine Lai-Han Leung. Distinct biological effect of inhibiting the metabolic pathway using active compounds derived from Chinese medicinal herbs in non-small cell lung cancer cells with different EGFR mutational profiles. [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 2255. doi:10.1158/1538-7445.AM2013-2255