Epigenetic regulator explains why some lung cancer patients become resistant to common therapeutics
Purdue University | 04-12-2022
Doctors typically treat people with non-small cell lung cancer, a prevalent and typically incurable type of cancer that makes up 80%-85% of lung cancers, with tyrosine kinase inhibitors, specifically epidermal growth factor receptor (EGFR) inhibitors. About 15%-20% of these patients will become resistant to these standard treatments, resulting in their eventual death.
Researchers understand part of the reason for this: The cells develop a mutation that leads to resistance. But about half of those resistant patients remain unexplained.
Andrea Kasinski, a cellular biologist, and her lab have discovered that some of the explanation is epigenetic. When cells lose the epigenetic regulator histone methyltransferase (KMT5C), genes that are normally repressed by KMT5C instead become expressed, leading to resistance to EGFR inhibitors. This understanding lays the groundwork for future therapeutics and gives researchers and doctors a deeper insight into the biology and progression of cancers, especially the role that epigenetic-modifying proteins play in drug resistance, a phenomenon that is not well understood.
Kasinski and her team identified the KMT5C gene using a global CRISPR-Cas9 screen after challenging the cells with an EGFR inhibitor. They selected cells that grew out and then identified the mutations, finding that KMT5C was the most significantly mutated gene in the screen.
They validated the results in other cell lines using genetic knockdown and chemical inhibition of KMT5C, leading them to discover that the gene MET, a prominent cancer gene, was upregulated, thereby contributing to resistance to therapeutics.
“For the majority of genes that contribute to cancer, we’re not sure how they work yet,” Kasinski said. “And for many, we don’t have a way to therapeutically target them. Research like this, that helps us understand how those genes work to determine cancer outcomes, adds to our understanding of the network. This knowledge will ultimately lead us to better therapeutics.”
Kasinski is an expert in how epigenetic factors, especially noncoding RNAs, affect cancer outcomes, including resistance to therapeutics. She is the William and Patty Miller Associate Professor in the Department of Biological Sciences in Purdue’s College of Science, as well as a researcher studying cell identity and signaling with the Purdue Center for Cancer Research. She is an expert in target discovery and characterization, delivery, and formulations, and in vivo disease models with the Purdue Institute for Drug Discovery.
The study is published in Cancer Research.
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