Bromocriptine sensitivity in bromocriptine-induced drug-resistant prolactinomas is restored by inhibiting FGF19/FGFR4/PRL.

in Journal of endocrinological investigation by Z Zhu, B Hu, D Zhu, X Li, D Chen, N Wu, Q Rao, Z Zhang, H Wang, Y Zhu

TLDR

  • The study is about a group of cells that produce too much of a hormone called prolactin. These cells are called prolactinomas. The study is trying to understand why some prolactinomas become resistant to a drug called bromocriptine (BRC). The study found that a gene called FGF19 is involved in this resistance. The study also found that a combination of BRC and a drug called fisogatinib (FISO) can be effective in treating BRC-resistant prolactinomas. The study has important implications for the treatment of prolactinomas and identifies several limitations and future research directions.

Abstract

At present, various treatment strategies are available for pituitary adenomas, including medications, surgery and radiation. The guidelines indicate that pharmacological treatments, such as bromocriptine (BRC) and cabergoline (CAB), are important treatments for prolactinomas, but drug resistance is an urgent problem that needs to be addressed. Therefore, exploring the mechanism of drug resistance in prolactinomas is beneficial for clinical treatment. In our research, BRC-induced drug-resistant cells were established. Previous RNA sequencing data and an online database were used for preliminary screening of resistance-related genes. Cell survival was determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence and Co-immunoprecipitation (Co-IP) were used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination was evaluated in drug-resistant cells and xenograft tumors in nude mice. Consistent with the preliminary results of RNA sequencing and database screening, fibroblast growth factor 19 (FGF19) expression was elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibited increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. After confirming that FGF19 binds to FGFR4 in prolactinoma cells, we found that FGF19/FGFR4 regulated prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. Regarding the effect of targeting FGF19/FGFR4 on BRC efficacy, FISO and BRC synergistically inhibited the growth of tumor cells, promoted apoptosis and reduced PRL levels. Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.

Overview

  • The study explores the mechanism of drug resistance in prolactinomas, specifically focusing on bromocriptine (BRC)-induced drug-resistant cells. The study uses RNA sequencing data and an online database for preliminary screening of resistance-related genes. Cell survival is determined by Cell Counting Kit-8 (CCK-8) assay, colony formation assays, and flow cytometry. Quantitative real-time polymerase chain reaction (qRT‒PCR), western blotting, immunohistochemistry, immunofluorescence, and Co-immunoprecipitation (Co-IP) are used to assess the molecular changes and regulation. The therapeutic efficacy of BRC and FGFR4 inhibitor fisogatinib (FISO) combination is evaluated in drug-resistant cells and xenograft tumors in nude mice. The primary objective of the study is to identify a new mechanism involved in the drug resistance of prolactinomas and to evaluate the efficacy of combination therapy targeting the pathway.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically focusing on the comparison between drug-sensitive and drug-resistant cells. The study identifies fibroblast growth factor 19 (FGF19) as a key resistance-related gene and finds that FGF19 expression is elevated in drug-resistant cells and tumor samples. With FGF19 silencing, drug-resistant cells exhibit increased sensitivity to BRC and decreased intracellular phosphorylated fibroblast growth factor receptor 4 (FGFR4) levels. The study also finds that FGF19/FGFR4 regulates prolactin (PRL) synthesis through the ERK1/2 and JNK signaling pathways. The study evaluates the therapeutic efficacy of targeting FGF19/FGFR4 and finds that FISO and BRC synergistically inhibit the growth of tumor cells, promote apoptosis, and reduce PRL levels.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study identifies a new mechanism involved in the drug resistance of prolactinomas, which could lead to the development of new treatment strategies. The study also evaluates the efficacy of combination therapy targeting the FGF19/FGFR4 pathway, which could be helpful for the treatment of BRC-induced drug-resistant prolactinomas. The study identifies several limitations, including the need for further validation of the findings in larger studies and the need to investigate the role of FGF19/FGFR4 in other types of pituitary adenomas. Future research directions could include exploring the role of FGF19/FGFR4 in other types of pituitary adenomas, investigating the long-term effects of combination therapy targeting the pathway, and evaluating the safety and efficacy of the therapy in clinical trials.
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