Sir Peter MacCallum Department of Oncology - Research Publications

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Author: Trigos, Anna × Author: Cullinane, Carleen × Author: Hannan, Katherine × Type: Journal Article ×

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    Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis
    Kusnadi, EP ; Trigos, AS ; Cullinane, C ; Goode, DL ; Larsson, O ; Devlin, JR ; Chan, KT ; De Souza, DP ; McConville, MJ ; McArthur, GA ; Thomas, G ; Sanij, E ; Poortinga, G ; Hannan, RD ; Hannan, KM ; Kang, J ; Pearson, RB (WILEY, 2020-11-02)
    Elevated ribosome biogenesis in oncogene-driven cancers is commonly targeted by DNA-damaging cytotoxic drugs. Our previous first-in-human trial of CX-5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA polymerase I (Pol I) transcription, revealed single-agent efficacy in refractory blood cancers. Despite this clinical response, patients were not cured. In parallel, we demonstrated a marked improvement in the in vivo efficacy of CX-5461 in combination with PI3K/AKT/mTORC1 pathway inhibitors. Here, we reveal the molecular basis for this improved efficacy observed in vivo, which is associated with specific suppression of translation of mRNAs encoding regulators of cellular metabolism. Importantly, acquired resistance to this cotreatment is driven by translational rewiring that results in dysregulated cellular metabolism and induction of a cAMP-dependent pathway critical for the survival of blood cancers including lymphoma and acute myeloid leukemia. Our studies thus identify key molecular mechanisms underpinning the response of blood cancers to selective inhibition of ribosome biogenesis and define metabolic vulnerabilities that will facilitate the rational design of more effective regimens for Pol I-directed therapies.
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    CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer
    Sanij, E ; Hannan, KM ; Xuan, J ; Yan, S ; Ahern, JE ; Trigos, AS ; Brajanovski, N ; Son, J ; Chan, KT ; Kondrashova, O ; Lieschke, E ; Wakefield, MJ ; Frank, D ; Ellis, S ; Cullinane, C ; Kang, J ; Poortinga, G ; Nag, P ; Deans, AJ ; Khanna, KK ; Mileshkin, L ; McArthur, GA ; Soong, J ; Berns, EMJJ ; Hannan, RD ; Scott, CL ; Sheppard, KE ; Pearson, RB (NATURE PUBLISHING GROUP, 2020-05-26)
    Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.