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Supplementary Figure from Loss of VOPP1 Contributes to BET Inhibitor Acquired Resistance in Non–Small Cell Lung Cancer Cells

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posted on 2023-04-03, 20:06 authored by Lin Sun, Qian Wu, Xia-Juan Huan, Chang-Qing Tian, Ying-Qing Wang, Ze-Hong Miao
Supplementary Figure from Loss of VOPP1 Contributes to BET Inhibitor Acquired Resistance in Non–Small Cell Lung Cancer Cells

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Science and Technology Commission of Shanghai Municipality (STCSM)

National Natural Science Foundation of China (NSFC)

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ARTICLE ABSTRACT

Inhibitors targeting bromodomain and extraterminal (BET) proteins are promising anticancer drugs. The emergence of drug resistance during treatments will impair their therapeutic effectiveness. To investigate the mechanisms of acquired resistance to BET inhibitors (BETi), we generated a series of drug-resistant sublines by exposing non–small cell lung cancer (NSCLC) NCI-H1975 cells to the BETi ABBV-075. These sublines displayed cross-resistance to other tested BETis, increased migration abilities, reduced growth rates accompanied by an increased proportion of cells in G1 phase and decreased apoptotic responses to BETis. Changes in RNA expression and gene mutation profiles in the resistant variants indicate that emergence of BETi resistance is multifactorial. Importantly, all the tested ABBV-075–resistant variants showed loss of vesicular overexpressed in cancer prosurvival protein 1 (VOPP1) and an increase in the antiapoptotic BCL-2 protein. By knockdown, knockout, and reconstitution of VOPP1 in resistant cells, their parental cells, and other NSCLC cells, we confirmed that the loss of VOPP1 contributed to BETi resistance. Moreover, knockout of VOPP1 in the parental cells caused the increased expression of BCL-2, and the latter directly mediated BETi resistance. Through combined treatments with BETis and BCL-2 inhibitors (BCL-2i), we demonstrated that BCL-2is synergistically sensitized resistant cells to BETis. Based on these results, for the first time, we establish a causal link from VOPP1 loss to BCL-2 gain and then to BETi resistance, which provides new insights into BETi resistance and paves the way for further testing to circumvent BETi resistance.

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