Melbourne Medical School Collected Works - Research Publications

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Author: Cameron, Donald × Author: McArthur, Grant × Author: Pearson, Richard × Type: Journal Article ×

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    Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling
    Quin, J ; Chan, KT ; Devlin, JR ; Cameron, DP ; Diesch, J ; Cullinane, C ; Ahern, J ; Khot, A ; Hein, N ; George, AJ ; Hannan, KM ; Poortinga, G ; Sheppard, KE ; Khanna, KK ; Johnstone, RW ; Drygin, D ; McArthur, GA ; Pearson, RB ; Sanij, E ; Hannan, RD (IMPACT JOURNALS LLC, 2016-08-02)
    RNA polymerase I (Pol I)-mediated transcription of the ribosomal RNA genes (rDNA) is confined to the nucleolus and is a rate-limiting step for cell growth and proliferation. Inhibition of Pol I by CX-5461 can selectively induce p53-mediated apoptosis of tumour cells in vivo. Currently, CX-5461 is in clinical trial for patients with advanced haematological malignancies (Peter Mac, Melbourne). Here we demonstrate that CX-5461 also induces p53-independent cell cycle checkpoints mediated by ATM/ATR signaling in the absence of DNA damage. Further, our data demonstrate that the combination of drugs targeting ATM/ATR signaling and CX-5461 leads to enhanced therapeutic benefit in treating p53-null tumours in vivo, which are normally refractory to each drug alone. Mechanistically, we show that CX-5461 induces an unusual chromatin structure in which transcriptionally competent relaxed rDNA repeats are devoid of transcribing Pol I leading to activation of ATM signaling within the nucleoli. Thus, we propose that acute inhibition of Pol transcription initiation by CX-5461 induces a novel nucleolar stress response that can be targeted to improve therapeutic efficacy.
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    Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines
    Young, RJ ; Waldeck, K ; Martin, C ; Foo, JH ; Cameron, DP ; Kirby, L ; Do, H ; Mitchell, C ; Cullinane, C ; Liu, W ; Fox, SB ; Dutton-Regester, K ; Hayward, NK ; Jene, N ; Dobrovic, A ; Pearson, RB ; Christensen, JG ; Randolph, S ; McArthur, GA ; Sheppard, KE (WILEY-BLACKWELL, 2014-07)
    We have investigated the potential for the p16-cyclin D-CDK4/6-retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma. In a cohort of 143 patients with primary invasive melanoma, we used fluorescence in situ hybridization to detect gene copy number variations (CNVs) in CDK4, CCND1, and CDKN2A and immunohistochemistry to determine protein expression. CNVs were common in melanoma, with gain of CDK4 or CCND1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN2A in 56%. Three-quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with poorer melanoma-specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN2A gene or loss of protein (p16(INK) (4A) ) predicted sensitivity to the CDK4/6 inhibitor PD0332991, while RB1 loss predicted resistance.