Metabolic reprogramming driven by IGF2BP3 promotes acquired resistance to EGFR inhibitors in non-small cell lung cancer

Acquired resistance represents a bottleneck for effective molecular targeted therapy in cancer of the lung. Metabolic adaptation is really a distinct hallmark of human cancer of the lung that may lead to acquired resistance. Within this study, we discovered a singular mechanism of acquired potential to deal with EGFR tyrosine kinase inhibitors (TKIs) mediated by IGF2BP3-dependent crosstalk between epigenetic modifications and metabolic reprogramming with the IGF2BP3-COX6B2 axis. IGF2BP3 was upregulated in TKI-resistant non-small cell cancer of the lung patients, and IGF2BP3 expression correlated with reduced overall survival. Upregulated expression from the RNA binding protein IGF2BP3 in cancer of the lung cells reduced sensitivity to TKI treatment and exacerbated the introduction of drug resistance via promoting oxidative phosphorylation (OXPHOS). COX6B2 mRNA bound IGF2BP3, and COX6B2 was needed for elevated OXPHOS and purchased EGFR-TKI resistance mediated by IGF2BP3. Mechanistically, IGF2BP3 certain to the 3′-untranslated region of COX6B2 within an m6A-dependent manner to improve COX6B2 mRNA stability. Furthermore, the IGF2BP3-COX6B2 axis controlled IACS-10759 nicotinamide metabolic process, which could alter OXPHOS and promote EGFR-TKI acquired resistance. Inhibition of OXPHOS with IACS-010759, a little-molecule inhibitor, led to strong growth suppression in vitro as well as in vivo inside a gefitinib-resistant patient-derived xenograft model. With each other, these bits of information claim that metabolic reprogramming through the IGF2BP3-COX6B2 axis plays a vital role in TKI resistance and confers a targetable metabolic vulnerability to beat acquired potential to deal with EGFR-TKIs in cancer of the lung.