Abstract 3780: Autophagy targeting therapies in NSCLC: Autophagy induction vs. inhibition in combination with erlotinib shows Torin1 can sensitize NSCLCs with KRAS mutations to Erlotinib

Abstract

Abstract In non-small cell lung cancer (NSCLC), therapies targeting the epidermal growth factor receptor (EGFR) are effective in the about 10% of cases that express mutant EGFR. The limited response of such therapies indicates the need to uncover additional therapeutic targets to increase the efficacy of EGFR targeted agents in a broader range of cases. One potential new targeted that may have therapeutic implications is the process of autophagy, which cells use to recycle proteins other cellular components. Currently, two opposing hypotheses exist concerning the role of autophagy in cancer. Autophagy may have tumor suppressive properties such as controlling cell growth, degrading damaged organelles, and serving as an alternate death mechanism. Conversely, it may function in tumor growth by enabling survival in conditions of low nutrients and oxygen, and protecting tumor cells against chemotherapy induced damage. The role of autophagy in cancer may also vary depending on cell type, tumor histology, oncogenotype, stage of tumor progression, or other factors. The type of treatment that will be most useful for the treatment of lung cancer will depend on which of these scenarios is most accurate in NSCLC cases. Approach: This study aims to analyze the role of autophagy in NSCLC by comparing autophagy inducing agents with an autophagy inhibitor for their ability to sensitize lung cancer cells to EGFR targeted therapy. A panel of NSCLC cell lines has been screened with an autophagy inhibitor (chloroquine) and autophagy inducers (Torin1 [Whitehead, DFCI] and rapamycin) alone and in combination with EGFR inhibitor erlotinib. Response to drug treatments was tested using a five day MTS assay for both single agent and combination treatments. Liquid colony formation assays confirmed the sensitization to erlotinib by autophagy inducers seen by MTS assay. The effects of drug treatments on autophagic flux were determined using a ‘tandem fluorescent’ LC3 protein reporter assay (ptfLC3, Yoshimori), in which the percent co-localization of mRFP and EGFP signals can be used to determine the relative levels of autophagosome formation and degradation (Kimura et al.(2007) Autophagy 3(5):452-60). Conclusions: Chloroquine, had little impact on sensitizing the lung cancer cell lines to erlotinib. Combinations with Torin1 or rapamycin resulted in 10-20 fold sensitization to erlotinib in a subset of NSCLC cell lines which had wild type EGFR and oncogenic KRAS or NRAS and wild type or mutant p53. These results indicate that autophagy induction and not autophagy inhibition, may be an effective targeted therapy in combination with erlotinib for certain cases of NSCLC. However, because sensitization occurred in only a small subset of lung cancer cell lines, there is a need to determine biomarkers that may be used to predict in which cases sensitization will most likely occur. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3780. doi:10.1158/1538-7445.AM2011-3780