Medical Biology - Research Publications

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Author: Chan, Keefe × Author: Cullinane, Carleen × End date: 2021 × Type: Journal Article ×

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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.
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    Regulation of PRMT5-MDM4 axis is critical in the response to CDK4/6 inhibitors in melanoma
    AbuHammad, S ; Cullinane, C ; Martin, C ; Bacolas, Z ; Ward, T ; Chen, H ; Slater, A ; Ardley, K ; Kirby, L ; Chan, KT ; Brajanovski, N ; Smith, LK ; Rao, AD ; Lelliott, EJ ; Kleinschmidt, M ; Vergara, IA ; Papenfuss, AT ; Lau, P ; Ghosh, P ; Haupt, S ; Haupt, Y ; Sanij, E ; Poortinga, G ; Pearson, RB ; Falk, H ; Curtis, DJ ; Stupple, P ; Devlin, M ; Street, I ; Davies, MA ; McArthur, GA ; Sheppard, KE (NATL ACAD SCIENCES, 2019-09-03)
    Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor-positive breast cancer and are currently in clinical development in melanoma, a tumor that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib and demonstrate that the activity of PRMT5, a protein arginine methyltransferase and indirect target of CDK4, is essential for CDK4/6 inhibitor sensitivity. By indirectly suppressing PRMT5 activity, palbociclib alters the pre-mRNA splicing of MDM4, a negative regulator of p53, leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 induces p21, leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treating naive and resistant models and also delays the emergence of resistance. Our studies have uncovered a mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide preclinical evidence that coinhibition of CDK4/6 and PRMT5 is an effective and well-tolerated therapeutic strategy. Overall, our data provide a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors, not only in melanoma but other tumor types, including breast, pancreatic, and esophageal carcinoma.