Abstract 4884: OXPHOS: A novel target for cancer therapy in oncogene addicted tumor

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.4884-4884
• Main Authors: Hirpara, Jayshree L., Qing, Jie Eu, Wong, Andrea, Ohi, Naoto, Takeshi, Tsunoda, Goh, Boon Cher, Pervaiz, Shazib
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-4884

Cancer cells are highly dependent on glycolysis over oxidative phosphorylation (OXPHOS). However, there is emerging evidence that (a) dysfunctional OXPHOS may be a major factor driving oncogene addiction and (b) feedback activation of the transcription factor STAT3 is a common surrogate survival pathway in oncogene addicted cancer cells. As such, invasive cancers exhibit enhanced oxidative phosphorylation, mitochondrial biogenesis and mitochondrial oxygen consumption rate. Therefore, inhibiting OXPHOS and STAT3 activity could have potential therapeutic implications for oncogene addicted and OXPHOS-dependent cancers. Here we report that oncogene addicted non-small cell lung carcinoma (NSCLC) cell line HCC827 and its gefitinib resistant clone and malignant melanoma cell line A375 and its vemurafanib resistant clone have significantly higher OXPHOS activity. In addition, these cells express higher level of the mitochondrial electron transport chain complex I protein (NDUFA9) and increased complex I activity as well as higher mitochondrial DNA copy number. Of note, significantly increased activity of STAT3 is detected in oncogene addicted cancer cells, and the increased mitochondrial oxygen consumption and complex I activity could be significantly inhibited by a novel small molecule inhibitor of STAT3, OPB-51602. The latter is shown to be an effect that might be independent of the STAT3 inhibitory activity of the small molecule compound. Most importantly, the novel STAT3 inhibitor showed strong activity in three different murine models of carcinogenesis as well as in patients treated with the STAT3 inhibitor. These data provide evidence that oncogene addicted cancer cells switch to OXPHOS over glycolysis and serve as proof of principle for identifying targeted new OXPHOS inhibitor in recalcitrant cancers. Citation Format: Jayshree L. Hirpara, Jie Eu Qing, Andrea Wong, Naoto Ohi, Tsunoda Takeshi, Boon Cher Goh, Shazib Pervaiz. OXPHOS: A novel target for cancer therapy in oncogene addicted tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4884.