Poster Presentation 30th Lorne Cancer Conference 2018

Targeting MDM4- mutant p53 axis in treatment resistant advanced prostate cancer (#246)

Dinesh Raghu 1 2 , Simon Keam 2 , Franco Caramia 2 , Elena Takano 2 , Jia Min Pang 2 , Panimaya Jeffreena Miranda 2 , Andrea Russo 3 , Giovanni Blandino 4 , Shahneen K Sandhu 2 , Stephen B Fox 2 , Sue Haupt 2 , Ygal Haupt 2
  1. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  3. Surgical pathology, Regina Elena Cancer Institute, Rome, Italy
  4. Oncogenomic and Epigenetic Unit, Italian National Cancer Institute, Rome, Italy

Prostate cancer (PC) is the most common cancer in men. Resistance to treatment frequently occurs in a proportion of PC patients with advanced disease1. We hypothesised that targeting the drivers of advanced PC is a strategic therapeutic approach. Loss of p53 tumour suppressor activity is common in cancers, including PC. P53 activity is frequently curbed either by excessive negative regulation by members of the MDM family, or through p53 mutation. P53 mutation is a metastatic driver of invasive disease, including metastatic PC6. Our lab has been interested in the capacity of abnormal activity of p53 and the MDM family to drive cancer. We and others have demonstrated an oncogenic role for the major p53 regulator MDM4, in breast cancer3, 4 and melanoma5. We have shown oncogenic MDM4 function both in cancers with wt p534 and mutant p533, albeit through distinct mechanisms.In the current study, we identified that MDM4 is elevated in advanced PC. A subset of these patients also harbour p53 mutations. We examined the role of MDM4-mutant p53 axis in PC. We demonstrated that targeting MDM4 by shRNA mediated knockdown inhibits the growth of PC cells in vitro and PC tumour formation in vivo. Notably, reactivating tumour suppressive function in mutant p53 using APR-246 in combination with targeting MDM4, compounded to inhibit the growth of PC. Overall, our findings demonstrate an oncogenic role for MDM4 in PC progression and the efficacy of targeting MDM4 either alone or in combination with mutant p53 re-activation as a novel approach to treat resistant advanced PC.

 References

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