Browsing by Author "Jette, Nicholas Ryan"

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    ATM-deficient cancer cells and targeted therapies
    (2018-07-09) Jette, Nicholas Ryan; Lees-Miller, Susan; Narendran, Aru; Senger, Donna L.; Bebb, Gwyn D.
    The driving principle behind precision medicine is to specifically target genetic variations that arise in tumorigenesis while leaving normal cells unaffected. Mutations in Ataxia Telangiectasia Mutated (ATM) may offer such a therapeutic target. ATM is mutated in a variety of tumor types and these mutations can lead to a dysfunctional protein, or protein deletion. ATM is an apex signaling kinase that responds to DNA double strand breaks, playing a direct role in DNA repair as well as the initiation of signaling cascades that can lead to cell cycle arrest and apoptosis. In recent years, several studies have shown that Poly ADP-Ribose Polymerase (PARP) inhibitors effectively target ATM-deficient tumors both invitro and invivo. These studies have been limited to mantle cell lymphoma, gastric cancer, colorectal cancer and breast cancer cell lines and the mechanism of sensitivity remains unclear. Here, I show that ATM-deficient lung and pancreatic cancer cell lines are sensitive to olaparib (a PARP inhibitor) and that ATM-deficient pancreatic cancer cell lines are sensitive to the PARP inhibitor Rucaparib as well as the ATR inhibitor VE-821. Using both lung and colorectal cancer cells, I also show that olaparib induces DNA damage and that olaparib causes an accumulation of G2 phase cells in ATM-deficient cells. Since olaparib is set to become a more commonly used chemotherapeutic, these findings are both important and relevant to its use in the clinic.