• Epigenetic regulator explains why some l

    From ScienceDaily@1:317/3 to All on Tue Apr 12 22:30:44 2022
    Epigenetic regulator explains why some lung cancer patients become
    resistant to common therapeutics

    Date:
    April 12, 2022
    Source:
    Purdue University
    Summary:
    Cellular biologists discover why some patients become resistant
    to standard treatments for nonsmall cell lung cancer.



    FULL STORY ========================================================================== Doctors typically treat people with nonsmall 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 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
    histone methyltransferase (KMT5C), genes that KMT5C were repressing
    instead become expressed, leading to resistance to epidermal growth
    factor receptor 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.

    "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." Purdue professor's expertise 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.

    Brief summary of methods Kasinski and her team identified the KMT5C
    gene using a global CRISPR-Cas9 screen after challenging the cells with
    an epidermal growth factor receptor 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. They used chromatin immunoprecipitation with
    an antibody for the methylation mark made by KMT5C to determine that
    an RNA that enhances MET expression is normally methylated and, thus,
    not expressed. When cells lose KMT5C, the RNA is expressed, leading to
    MET expression and the subsequent resistance to therapeutics.

    This study was funded in part by the National Institutes of Health, as
    well as grants from the Purdue Research Foundation, the Purdue Center
    for Cancer Research and Purdue University.


    ========================================================================== Story Source: Materials provided by Purdue_University. Original written
    by Brittany Steff.

    Note: Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Arpita S. Pal, Alejandra Agredo, Nadia A. Lanman, Jihye Son,
    Ikjot Singh
    Sohal, Manvir Bains, Chennan Li, Jenna Clingerman, Kayla Gates,
    Andrea L.

    Kasinski. Loss of KMT5C Promotes EGFR Inhibitor Resistance in NSCLC
    via LINC01510-Mediated Upregulation of MET. Cancer Research, 2022;
    OF1 DOI: 10.1158/0008-5472.CAN-20-0821 ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/04/220412161556.htm

    --- up 6 weeks, 1 day, 10 hours, 51 minutes
    * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)