INTERPLAY BETWEEN MDM2 AND TFAM REGULATES OXIDATIVE PHOSPHORYLATION IN DRUG-RESISTANT ONCOGENE-ADDICTED CANCERS

Tyrosine kinase inhibitors (TKI) remain the first-line treatment for most oncogene-addicted cancers. However, prolonged exposure to TKI could lead to development of resistance. There is mounting evidence of OXPHOS dependency as a mechanism of TKI resistance, but the cause of this metabolic switch remains elusive. Here, we report a novel mechanism involving mitochondria-bound MDM2 (mtMDM2) in driving OXPHOS regulation in TKI-resistant cancers through an interaction with TFAM. This phenomenon involves the mitochondrial-cytoplasm shuttling of MDM2 in a p53-independent manner, which leads to enhanced mitochondrial biogenesis via TFAM transcriptional machinery. Furthermore, we describe an increase in AKT signalling in TKI-resistant cancers that contributed to protein stability of MDM2 through phosphorylation. Inhibition of AKT leads to decrease in MDM2 Ser166 phosphorylation and increase mitochondria localisation in TKI-resistant cells. Collectively, we describe a novel observation that altered metabolism and TKI resistance in cancer cells could be mediated by MDM2 phosphorylation and mitochondria localization.

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• EU JIE QING

• mdm2; metabolism; drug resistance; tfam; oncogene addicted