MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer

Abstract

Background: Resistance to endocrine therapy is a major clinical challenge in the management of oestrogen receptor (ER)-positive breast cancer. In this setting, p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment-resistant ER-positive breast cancer. Methods: We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate antitumour effects in p53 wildtype and p53 mutant ER-positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and endocrine-resistant ER-positive breast cancer. Results: We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/ 6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant-resistant patient-derived xenograft model. Conclusions: We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine-resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programmes.

MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer

“…Part of the p53 tumour suppressive activity therefore operates via p107 and p130 cooperating with pRb to control entry into the cell cycle from G1 (although pRb appears to play the dominant role) and also through p107/p130-mediated cell cycle arrest in G2/M. Consistent with this, in our recent examination of the activity of the MDM2i NVP-CGM097 in ER+ breast cancer models, we were able to observe accumulation of cells in both the G1 and G2/M phases of the cell cycle after p53 activation (29).…”

“…It is perhaps not surprising, and quite elegant, that the cell would find something useful for all of the MDM2 protein produced by p53 activation to do whilst p53 activity is still required! Interestingly, we recently showed that in a cell line model of palbociclib resistance, treatment with MDM2i did indeed result in a significant accumulation of cells in G2/M but not in G1/S as we had observed in cells sensitive to palbociclib (29).…”

Breast Cancer Resistance to Cyclin-Dependent Kinases 4/6 Inhibitors: Intricacy of the Molecular Mechanisms

“…Abnormal regulations of upstream and Downstream kinases: CCNE1/CDK2, CDK7, E2F, INK, PTEN, Smad-TGF-β pathway which are involved in the progression of cell cycle, as shown in Figure 1 , are responsible for resistance to CDK4/6 inhibitors ( 12 , 15 , 17 , 26 , 35 – 60 ); 4. Activation of alternate genes like HDACS, WEE1, MDM2, partly help the cancer cell escape from the drugs work ( 61 – 67 ).…”

“…Therefore, the use of MDM2 inhibitors may reverse cellular resistance to CDK4/6 inhibitors, and this has been in human liposarcoma ( 66 ). Indeed, the MDM2 inhibitor, CGM097, in combination with a CDK4/6 inhibitor palbociclib and fulvestrant has shown promising therapeutic benefits in reversing the tumor resistance to CDK4/6 inhibitors and to endocrine therapy ( 67 ) ( Figure 2 , Table 1 ).…”

Associations of MDM2 and MDM4 Polymorphisms with Early-Stage Breast Cancer

“…In spite of this fact, protein p53 encoded by wild-type TP53 can be functionally inactivated by abnormal structure or elevated levels of MDM2 and MDM4 [ 9 , 20 , 21 , 22 , 23 ]. Consequently, blocking MDM2 and MDM4 has been proposed as a cancer treatment strategy [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ].…”