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|Ref Type||Journal Article|
|Authors||Lu J, McEachern D, Li S, Ellis MJ, Wang S|
|Title||Reactivation of p53 by MDM2 Inhibitor MI-77301 for the Treatment of Endocrine-Resistant Breast Cancer.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Endocrine therapy has been highly effective for the treatment of estrogen receptor-positive breast cancer, but endocrine resistance develops in a significant proportion of patients. In an effort to develop novel therapeutic strategies for the treatment of endocrine-resistant breast cancer, we have evaluated a potent and specific MDM2-p53 interaction inhibitor, MI-77301, which has been advanced into clinical development, for its therapeutic potential and mechanism of action in vitro and in vivo in WHIM9 and WHIM18 patient-derived xenograft (PDX) models. Both WHIM9 and WHIM18 PDX models exhibit estradiol-independent tumor growth and are resistant to fulvestrant, a highly effective and selective estrogen receptor degrader (SERD). MI-77301 activates wild-type p53 in WHIM9 and WHIM18 cells in vitro and in xenograft tumor tissues in vivo, and it effectively induces upregulation of p21 and cell-cycle arrest in vitro in both models. Although fulvestrant fails to inhibit tumor growth in either of the xenograft models, MI-77301 is highly effective in inhibition of tumor growth at a well-tolerated dose schedule. This study provides a preclinical rationale for evaluation of MI-77301 or other MDM2 inhibitors as a new therapeutic strategy for the treatment of endocrine-resistant breast cancer retaining wild-type p53. Mol Cancer Ther; 15(12); 2887-93. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
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|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
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|TP53 wild-type||breast cancer||predicted - sensitive||SAR405838||Preclinical - Pdx||Actionable||In a preclinical study, SAR405838 (MI-77301) induced p53 signaling and inhibited tumor growth in patient-derived xenograft models of endocrine therapy-resistant breast cancer with wild-type TP53, and induced cell-cycle arrest and inhibited growth of patient-derived endocrine therapy-resistant breast cancer cells in culture (PMID: 27765850).||27765850|