Abstract 1327: Role of intra-tumoral bacteria in EGFR-tyrosine kinase inhibitor resistance

Abstract

Abstract Mutations of the epidermal growth factor receptor (EGFR) are the most common group of actionable mutations in lung cancer, and they predict response to EGFR-tyrosine kinase inhibitos (EGFR-TKIs). The third-generation EGFR-TKI osimertinib is the standard of care for first-line treatment of patients with advanced EGFR-mutated lung cancer. Although most lung cancers with EGFR-mutation respond to osimertinib, resistance is eventually observed in all patients, and there are no approved targeted therapies once resistance to osimertinib occurs. Mechanisms of resistance to osimertinib are poorly understood and involve both EGFR and non-EGFR related pathways. Intra-tumoral bacteria are emerging as a cause of therapy resistance in cancer.Intra-tumoral bacteria have been reported in many cancers and emerging evidence suggests that the tumor microbiome plays an important role in drug resistance in a variety of cancers. But the link between intra-tumoral bacteria and therapy resistance in lung cancer remains elusive. We previously described the tumor microbiome identified within a cohort of non-small cell lung cancers. In order to determine if intra-tumoral bacteria within lung adenocarcinoma patient with EGFR mutation could play role on the resistance to EGFR-TKIs, such as osimertinib and erlotinib, we used a bacterial pre-conditioned medium (PCM) screening system which utilized various bacteria identified in lung cancer specimens. We used a cell viability evaluation method in GFP-labeled PC9 cells (EGFR Ex19del) to identify the bacterial PCM that may lead to resistance to EGFR-TKIs. We found that PCM from Chryseobacterium indologenes (C-PCM) markedly rescued PC9 cells from osimertinib or erlotinib treatment. We also found that proteinase K treatment eliminated the rescue of C-PCM on EGFR-TKI treatment, suggesting that a proteins within C-PCM are responsible for its effect of EGFR-TKI treatment. Mass spectrometry (MS) analysis showed that C-PCM does not degrade osimertinib or erlotinib, suggesting that C-PCM mediated resistance does not occur through drug degradation. Western blot analysis showed that C-PCM does not affect EGFR, phospho-EGFR, or AKT expression level but C-PCM significantly increased AKT phosphorylation level. Our current studies indicated that intra-tumoral bacteria within lung adenocarcinoma patient may leads to resistance to osimertinib and erlotinib. Further mechanistic studies of C-PCM mediated resistance are under way and may lead to new therapies to overcome osimertinib-resistance. Citation Format: Wendong Li, Aviva Rotter-Maskowitz, Ting Sun, Keqiang Zhang, Ravid Straussman, Dan Raz. Role of intra-tumoral bacteria in EGFR-tyrosine kinase inhibitor resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1327.