Strong p53 and MDM2 staining is usually observed in both WHIM9 and WHIM18 tumor tissues at 6 h but the staining becomes much weaker at the 24 h time-point

Strong p53 and MDM2 staining is usually observed in both WHIM9 and WHIM18 tumor tissues at 6 h but the staining becomes much weaker at the 24 h time-point. xenograft models, MI-77301 is usually highly effective in inhibition of tumor growth at a well-tolerated dose-schedule. This study provides a preclinical rational 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. and acquired resistance (1, 2). A number of resistance mechanisms have been recognized, including deregulation of various components of the ER pathway itself, alterations in cell cycle and cell survival signaling pathways, and activation of escape pathways that can provide tumors with alternate proliferation and survival stimuli (1, 2). For example, increased expression or signaling of growth factor receptor pathways, especially the EGFR/HER2 pathway, has been associated with both experimental and clinical resistance to endocrine therapy (3-5) and has led to the development of clinical treatment strategies combining an endocrine therapy with a targeted agent that blocks the EGFR/HER2 pathway (6, 7). In addition to dysregulation in growth factor receptor pathways, alterations in the cyclin-CDK-RB (cyclin-dependent kinase-retinoblastoma protein) pathway, which lead to loss of control of the cell cycle, are common in human breast malignancy (8, 9) (10, 11). A specific CDK4/CDK6 inhibitor, PD 0332991 (palbociclib), has been observed in preclinical studies to be particularly effective against ER-positive breast malignancy cell lines (12), including cell lines resistant to endocrine therapy, and shows synergy with tamoxifen(12). Recent clinical data have shown that the combination of palbociclib with letrozole, an AI, has greatly improved progression-free survival in ER-positive metastatic breast malignancy over letrozole alone(13). This was the basis for an accelerated FDA approval of the palbociclib-letrozole combination for the treatment of postmenopausal women with ER-positive, HER2-unfavorable advanced breast cancer as an initial CACNA1G endocrine-based therapy for metastatic disease(14). Despite these great improvements in development of new therapeutic strategies to overcome endocrine resistance, there is still a need to develop new approaches for the treatment of ER-positive, metastatic breast cancer, particularly endocrine-resistant breast cancer. While the median disease-free survival time with the combination treatment of palbociclib and letrozole in ER-positive metastatic breast cancer is greatly improved over treatment with letrozole alone, it remains only 20 months (13). Recently, a panel of patient-derived xenograft models, referred as Washington University or college Human in Mouse (WHIM) lines, were developed from breast cancer patients with poor-prognosis, treatment-resistant disease (15). These WHIM lines were characterized by whole-genome sequencing and were compared to originating tumors from patients, which showed that structural and copy number aberrations were retained with high fidelity in these models (15). These WHIM lines therefore provide Parecoxib a set of excellent models with which to evaluate novel therapeutics for the treatment of breast cancer patients with poor-prognosis, treatment-resistant disease. Interestingly, a much higher percentage of these WHIM lines contains a wild-type p53 status than previously established breast malignancy cell lines. While only the MCF-7 cell collection retains a wild-type p53 status among a large number of human breast malignancy cell lines established in the past,. approximately one third (7 out of 22) of the WHIM lines contains wild-type p53 (15). This suggests the possibility that reactivation of wild-type p53 could be an effective therapeutic strategy for Parecoxib the treatment of a significant proportion of poor-prognosis, treatment-resistant breast cancer patients. To test this possibility, we evaluated the therapeutic potential and mechanism of action of MI-77301 (also known as SAR405838) (16), a potent and specific MDM2 inhibitor currently in clinical development, using two WHIM lines, WHIM9 and Parecoxib WHIM18, which contain wild-type p53. MI-77301 binds to MDM2 with a high affinity (Ki = 0.88 nM) and blocks both the interaction of MDM2 with p53 and the MDM2-mediated p53 degradation, leading to activation of wild-type p53 in cells (16). WHIM9 has a highly overexpressed, wild-type ESR1 and WHIM18 contains an ESR1-YAP1 fusion gene.(15). Both these WHIM lines show estradiol-independent growth in mice and are unresponsive to treatment with fulvestrant, a highly potent and selective estrogen receptor degrader (SERD) which has been used as a second-line treatment for hormone receptor positive metastatic breast cancer. Our data show that MI-77301 effectively activates p53 and and completely inhibits tumor growth in both models without any signs of toxicity. This suggests that MDM2 inhibitors should be clinically Parecoxib evaluated as a new.