Loss of VOPP1 Contributes to BET Inhibitor Acquired Resistance in Non-Small Cell Lung Cancer Cells

by Selleckchem | Aug 01 2023

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.

Implications: 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.

Comments:

The findings described in the passage suggest that acquired resistance to BET inhibitors (BETi) in non-small cell lung cancer (NSCLC) cells is a multifactorial process involving various molecular changes. The researchers generated drug-resistant sublines of NSCLC NCI-H1975 cells by exposing them to the BETi ABBV-075. These resistant sublines exhibited cross-resistance to other BETis, increased migration abilities, reduced growth rates, an accumulation of cells in the G1 phase of the cell cycle, and decreased apoptotic responses to BETis.

The analysis of RNA expression and gene mutation profiles in the resistant variants indicated that the development of BETi resistance involves multiple factors. Notably, all the tested ABBV-075-resistant variants showed a loss of vesicular overexpressed in cancer prosurvival protein 1 (VOPP1) and an increase in the antiapoptotic BCL-2 protein. The researchers confirmed the contribution of VOPP1 loss to BETi resistance through knockdown, knockout, and reconstitution experiments in both resistant cells and parental cells, as well as other NSCLC cells. Additionally, the knockout of VOPP1 in the parental cells led to increased BCL-2 expression, and BCL-2 directly mediated BETi resistance.

To address this acquired resistance, the researchers explored combined treatments using BETis and BCL-2 inhibitors (BCL-2i). They found that BCL-2is synergistically sensitized the resistant cells to BETis, suggesting a potential strategy to overcome BETi resistance.

Overall, this study establishes a causal link between the loss of VOPP1, the gain of BCL-2, and BETi resistance in NSCLC cells. These findings provide new insights into the mechanisms of BETi resistance and offer a basis for further investigation aimed at circumventing this resistance.