Potential Mechanism for Drug Resistance Identified in Ovarian Cancer


A new study is suggesting that combining BET inhibitors with other agents targeting protein kinases might make them more effective in treating cancer.

A new study is suggesting that combining BET inhibitors with other agents targeting protein kinases might make them more effective in treating cancer.   

Researchers at Fox Chase Cancer Center are reporting in Cell Reports that they have conducted a series of studies demonstrating that single-agent treatment with bromodomain and extra-terminal domain (BET) inhibitor therapies may not provide durable therapeutic response in ovarian cancer and will likely require combination therapies targeting protein kinase signaling.

The investigators report that epigenetic proteins involved in chromatin remodeling, such as the BET bromodomain protein BRD4, are now part of an exciting new class of targeted therapies against cancer. It has been theorized BRD4 overexpression may promote tumor growth through the enhancement of transcription of key oncogenes. Currently, BET inhibitor therapies are being investigated for their ability to combat numerous solid cancers.

The researchers report BET inhibitors, drugs that block the function of BET bromodomain proteins in cancer cells, appear to have limited success as single agents in ovarian cancer due to reprogramming of the protein kinome. Subsequently this leads to drug resistance. In their current investigation, they demonstrated that ovarian cancer cells could bypass BET inhibitor therapies by activating networks of protein kinases.

“Small-molecule BET inhibitors are actively being pursued in clinical trials for a variety of cancers as part of a push toward precision medicine. This study sought to determine what might lead to resistance in ovarian cancer,” said James Duncan, PhD, Assistant Professor at Fox Chase Cancer Center, Philadelphia, in a news release.

Researchers used a mass spectrometry-based method for this study that globally measured protein kinase signaling in a panel of ovarian cancer cell lines following BET inhibitor therapy. They found that the cells became resistant to the BET inhibitor treatment due to increased activity of a protein kinase network involved in cancer cell survival.

Duncan and his team evaluated the consequence of BET protein inhibition on kinase signaling and explored the role of kinome reprogramming in the acquisition of resistance to BET inhibitors by taking a chemical proteomics approach.

They report a mechanism of resistance to BET inhibitors involves the activation of receptor tyrosine kinases (RTKs) and downstream signaling by phosphatidylinositol 3-kinase (PI3K), AKT, and ERK. The researchers write that ovarian cancer cells chronically exposed to JQ1, which is a thienotriazolodiazepine and a potent inhibitor of the BET family of bromodomain, acquired sensitivity to combination therapies, which targeted RTKs, PI3K, or mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) pathways.

Combining other kinase inhibitors along with BET inhibitors may be the key in treating a difficult disease such as ovarian cancer.


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