Acquired resistance represents a bottleneck for effective molecular targeted therapy in lung cancer. Metabolic adaptation is a distinct hallmark of human lung cancer that might contribute to acquired resistance. In this study, we discovered a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by IGF2BP3-dependent crosstalk between epigenetic modifications and metabolic reprogramming through the IGF2BP3-COX6B2 axis. IGF2BP3 was upregulated in TKI-resistant non-small cell lung cancer patients, and high IGF2BP3 expression correlated with reduced overall survival. Upregulated expression of the RNA binding protein IGF2BP3 in lung cancer cells reduced sensitivity to TKI treatment and exacerbated the development of drug resistance via promoting oxidative phosphorylation (OXPHOS). COX6B2 mRNA bound IGF2BP3, and COX6B2 was required for increased OXPHOS and acquired EGFR-TKI resistance mediated by IGF2BP3. Mechanistically, IGF2BP3 bound to the 3’-untranslated region of COX6B2 in an m6A-dependent manner to increase COX6B2 mRNA stability. Moreover, the IGF2BP3-COX6B2 axis regulated nicotinamide metabolism, which can alter OXPHOS and promote EGFR-TKI acquired resistance. Inhibition of OXPHOS with IACS-010759, a small-molecule inhibitor, resulted in strong growth suppression in vitro and in vivo in a gefitinib-resistant patient-derived xenograft model. Collectively, these findings suggest that metabolic reprogramming by the IGF2BP3-COX6B2 axis plays a critical role in TKI resistance and confers a targetable metabolic vulnerability to overcome acquired resistance to EGFR-TKIs in lung cancer.
Technical efficiency (TE) and total factor productivity (TFP) are important criteria to ensure the enhancement of the quality and efficiency of state-owned enterprises (SOEs) and function as important indicators to assess the quality of their accomplishments. The purpose of this study is to explore whether the efficiency of SOEs is higher or lower than that of private enterprises. Transcendental logarithmic production function and stochastic frontier analysis (SFA) are used to assess the TE and TFP of listed central SOEs, local SOEs, and private enterprises, the data of which were taken from 2006–2020. The results show that the sampled private enterprises had the highest average TE during the study period, followed by the central and local SOEs. The private enterprises also had the highest average TFP growth rate, followed by the local and central SOEs. The TFP decompositions show that the TE change (TEC) and technical change (TC) indices of the SOEs were lower than those of the private enterprises. The TC, TEC, and scale change (SC) are limiting the TFP growth rates of the SOEs in labor-intensive industries. The SC of the SOEs has changed less than that of private enterprises in the sampled capital-intensive industries. Northern and southern China had the highest rates of TE and TFP growth. Indeed, this paper measures and decomposes TFP, and analyzes the efficiency of SOEs and private enterprises in different industries and regions in an international context.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.