Abstract 371: Developing small molecule therapeutics to target AKT signaling in non-small cell lung cancer

Abstract

Abstract Lung cancer remains a leading public health problem which is evidenced by its increasing death rate. Platinum-based chemotherapy is the first-line of treatment for patients in advanced stages of non-small cell lung cancer (NSCLC), however the success rates are not quite impressive. Hence, developing individualized treatment strategies for metastatic lung cancer gains momentum, such as Tyrosine kinase inhibitors erlotinib and gefitinib, or ALK inhibitors ceritinib and alectinib are commonly used in the clinic. Recent reports suggest that pAKT(ser473) is highly expressed in NSCLC and higher nuclear expression of pAKT correlated with poor prognosis and an independent prognostic marker for survival. Our lab is interested to develop novel small molecules which specifically inhibit AKT signaling in NSCLC. Structure-activity relationship (SAR) studies in our laboratory have recently ideintifed one such compound, AKS-407, that effectively inhibited cell growth at nanomolar concentration in NSCLC cell lines (A549 and H460; 250nM). Molecular studies revealed AKS-407 inhibited AKT signaling by down regulating pAKT(ser473) expression and downstream events including NFκB activation, BCl-2 expression in both the cell lines. As signaling through AKT regulates epithelial-mesenchymal transition (EMT) in NSCLC, we determined the effect of AKS-407 on EMT phenotype on NSCLC cells. Treatment of AKS-407 inhibited the mesenchymal markers includes snail, MMP9, N-cadherin, β-catenin and vimentin expression that resulted in blocking invasion and migration of A549 and H-460 cells. These results suggest AKS-407 to be a promising small molecule targeting AKT signaling pathway which remains an important target for the development of effective treatment of metastatic NSCLC. Validating in-vivo efficacy of this potential drug candidate would further support our overall goal of the study. Citation Format: Balaji Chandrasekaran, Deeksha Pal, Venkatesh Kolluru, Srinivasa R. Ramisetti, Arun K. Sharma, Murali Ankem, Chendil Damodaran. Developing small molecule therapeutics to target AKT signaling in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 371. doi:10.1158/1538-7445.AM2017-371