MDM2 Inhibition Sensitizes Prostate Cancer Cells to Androgen Ablation and Radiotherapy in a p53-Dependent Manner.
Increased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer.



The effect of MDM2 inhibition by MI-219 was assessed in vitro and in vivo with mouse xenograft models across multiple prostate cancer cell lines containing varying p53 functional status.



MDM2 inhibition by MI-219 resulted in dose- and time-dependent p53 activation and decreased clonogenic cell survival after radiation in a p53-dependent manner. Mechanistically, radiosensitization following inhibition of MDM2 was largely the result of p53-dependent increases in apoptosis and DNA damage as evidenced by Annexin V flow cytometry and γ-H2AX foci immunofluorescence. Similarly, treatment with MI-219 enhanced response to antiandrogen therapy via a p53-dependent increase in apoptotic cell death. Lastly, triple therapy with radiation, androgen deprivation therapy, and MI-219 decreased xenograft tumor growth compared with any single- or double-agent treatment.



MDM2 inhibition with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation, antiandrogen therapy, and the combination. These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer.



The combination of radiotherapy and androgen deprivation therapy is a standard treatment option for men with high-risk prostate cancer. Despite improvements in outcomes when androgen deprivation therapy is added to radiation, men with high-risk prostate cancer have significant risk for disease recurrence, progression, and even death within the first 10 years following treatment. We demonstrate that treatment with MI-219 (an inhibitor of MDM2) results in prostate cancer cell sensitization to radiation and androgen deprivation therapy in vitro and in vivo. Triple therapy with MI-219, radiation, and androgen deprivation therapy dramatically decreased tumor growth compared with any single- or double-agent therapy. These findings provide evidence that inhibition of MDM2 is a viable means by which to enhance the efficacy of both radiation and androgen deprivation therapy and thereby improve outcomes in the treatment of prostate cancer. As such, further investigation is warranted to translate these findings to the clinical setting.
Departments of Radiation Oncology, Urology, and Medicine, University of California at San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI. Electronic address: felix.feng@ucsf.edu.
Felix Y
FY
Feng
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
Yu
Y
Zhang
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
Vishal
V
Kothari
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
Joseph R
JR
Evans
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
William C
WC
Jackson
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
Wei
W
Chen
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
Skyler B
SB
Johnson
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI.
Connor
C
Luczak
Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA; Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan, Ann Arbor, MI, USA.
Shaomeng
S
Wang
Department of Radiation Oncology, University of Michigan, Ann Arbor, MI; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address: dhamm@umich.edu.
Daniel A
DA
Hamstra
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011836:Radiation Tolerance / Q000235:genetics; D011839:Radiation, Ionizing; D013141:Spiro Compounds / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000726:Androgen Antagonists; D000970:Antineoplastic Agents; D007211:Indoles; C574930:MI-219; D047428:Protein Kinase Inhibitors; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2