Abstract 4631: Pharmacologic inhibition of NF-kappaB overcomes de novo resistance to erlotinib in models of EGFR-mutant lung adenocarcinoma.

Abstract

Abstract Treatment of patients with lung cancers that harbor activating mutations in the kinase domain of EGFR (e.g. L858R, in frame Exon19 deletion), which account for 15-20% of lung adenocarcinomas, with the EGFR tyrosine kinase inhibitor (TKI) erlotinib, causes tumor regression in many patients. However, the magnitude of tumor regression is variable and responses are short-lived with a median duration of 9-12 months. Thus inhibition of mutant EGFR activity by treatment with erlotinib results in incomplete responses and is not curative in the majority of EGFR-mutant lung cancer patients. While mechanisms of acquired resistance to EGFR TKI treatment are well defined, mechanisms of de novo resistance, or incomplete initial response to EGFR TKI therapy, remain uncharacterized. We recently identified activation of the NF-kB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) signaling pathway as a key mediator of de novo resistance to EGFR TKI therapy in cell lines and tumor xenograft models of lung cancer. Furthermore, patients with EGFR-mutant lung cancers that demonstrate elevated IkB (NF-kB inhibitor) expression, and consequently low NF-kB activity, exhibit improved responses to EGFR TKIs compared to patients with low IkB levels. NF-kB is a family of transcription factors that regulates numerous biological processes, including cell proliferation and apoptosis, as well as a critical mediator of both innate and adaptive immune cell activity. We hypothesized that pharmacologic inhibition of NF-kB activity would enhance the efficacy of EGFR TKI in EGFR-mutant lung cancer. Using a novel rel (reticuloendotheliosis) inhibitor of NF-kB, PBS-1086 (rel∼MD, Inc.), we found that treatment of human lung cancer cells and tumor xenografts that harbor an EGFRL858R activating mutation (11-18), yet are EGFR TKI resistant, with erlotinib in combination with PBS-1086 induces tumor cell apoptosis and tumor regression. Erlotinib + PBS-1086 treatment results in decreased binding of the NF-kB subunit RelA to the IL6 promoter and a significant decrease in IL6 mRNA expression. IL6 has previously been shown to promote EGFR-mutant lung adenocarcinoma cell proliferation and survival, and its downregulation by PBS-1086 represents a possible mechanism of action of the compound. Using CC10-rtTA; Tet-Op-EGFR-mutant transgenic mouse models of lung adenocarcinoma, we have shown that treatment of mice with PBS-1086 enhances erlotinib-induced tumor regression. We believe that these results will guide future clinical trials of NF-kB inhibitors in combination with erlotinib to improve outcomes in selected EGFR-mutant lung cancer patients. Citation Format: Collin M. Blakely, Victor Olivas, Jie Zhang, Trever G. Bivona. Pharmacologic inhibition of NF-kappaB overcomes de novo resistance to erlotinib in models of EGFR-mutant lung adenocarcinoma. [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 4631. doi:10.1158/1538-7445.AM2013-4631