Abstract 5535: Effect of LKB1 activity on the sensitivity to PI3K/mTOR inhibitor in non-small-cell lung cancer

Abstract

Abstract The serine-threonine liver kinase B1 (LKB1, also called STK11) is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival and polarity. Germline mutation of LKB1 causes Peutz-Jeghers syndrome, which is an autosomal dominant disease characterized by mucocutaneous pigmentation and hamartomatous polyps. In non-small-cell lung cancer (NSCLC), LKB1 is frequently rendered non-functional, either through mutation or down regulation. As a tumor suppressor and a protein whose function is lost, identifying pathways that are activated with LKB1 loss may be the only way to target such tumors. Some previous studies have suggested that inhibition of mTOR, a growth promoting pathway negatively regulated by LKB1, as a potential target in LKB1 mutant NSCLC. In this study, we investigated the effect of LKB1 activity on the sensitivity to a PI3K/mTOR inhibitor using four LKB1 mutant NSCLC cell lines to which LKB1 gene was transduced and one LKB1 wild type NSCLC cell line in which LKB1 gene was knocked out by CRISPR technology. Transduction of LKB1 resulted in significant resistance to a PI3K/mTOR inhibitor in two of the four LKB1 add-back cell lines, while knocking out LKB1 in the LKB1 wild type cell line induced PI3K/mTOR inhibitor sensitivity. The mechanism behind these observed results appears to be through regulation of phosphorylation of AKT. The presence of LKB1 led to a persistent AKT phosphorylation even in the presence of the PI3K/mTOR inhibitor, both in add back cell and wild type cells. Our data suggest that the identification of LKB1 activity may be a promising biomarker for the sensitivity to PI3K/mTOR inhibition. Further investigation into the mechanism of LKB1 loss and increased sensitivity to inhibition of the PI3K and mTOR pathways is warranted. Citation Format: Takehito Shukuya, Tadaaki Yamada, Michael J. Koenig, Mohammad A. Rahman, Joseph M. Amann, David P. Carbone. Effect of LKB1 activity on the sensitivity to PI3K/mTOR inhibitor 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 5535. doi:10.1158/1538-7445.AM2017-5535