Dose and Schedule Determine Distinct Molecular Mechanisms Underlying the Efficacy of the p53–MDM2 Inhibitor HDM201

Abstract

Activation of p53 by inhibitors of the p53-MDM2 interaction is being pursued as a therapeutic strategy in p53 wild-type cancers. Here, we report distinct mechanisms by which the novel, potent, and selective inhibitor of the p53-MDM2 interaction HDM201 elicits therapeutic efficacy when applied at various doses and schedules. Continuous exposure of HDM201 led to induction of p21 and delayed accumulation of apoptotic cells. By comparison, high-dose pulses of HDM201 were associated with marked induction of PUMA and a rapid onset of apoptosis. shRNA screens identified PUMA as a mediator of the p53 response specifically in the pulsed regimen. Consistent with this, the single high-dose HDM201 regimen resulted in rapid and marked induction of PUMA expression and apoptosis together with downregulation of Bcl-xL Knockdown of Bcl-xL was identified as the top sensitizer to HDM201, and Bcl-xL was enriched in relapsing tumors from mice treated with intermittent high doses of HDM201. These findings define a regimen-dependent mechanism by which disruption of MDM2-p53 elicits therapeutic efficacy when given with infrequent dosing. In an ongoing HDM201 trial, the observed exposure-response relationship indicates that the molecular mechanism elicited by pulse dosing is likely reproducible in patients. These data support the clinical comparison of daily and intermittent regimens of p53-MDM2 inhibitors. Pulsed high doses versus sustained low doses of the p53-MDM2 inhibitor HDM201 elicit a proapoptotic response from wild-type p53 cancer cells, offering guidance to current clinical trials with this and other drugs that exploit the activity of p53. .

The relationship between TRAF6 and tumors

“…However, the ring domain-containing E3s also play a carcinogenic role. To date, there are also some specific RING E3 inhibitors (e.g., IAP and MDM2) that have entered clinical research and provide a promising strategy for cancer chemotherapy and prevention [107][108][109].…”

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

“…Importantly, our data show that combination of NVP-CGM097 with fulvestrant, which is not associated with haematological adverse effects, has a highly similar response profile to combination with CDK4/6 inhibition in terms of the key molecular pathways affected. It is currently unclear as to whether NVP-CGM097 itself will continue in development; however, a range of next-generation MDM2 inhibitors with improved tolerability are in development [ 38 ]. Our results demonstrate that MDM2 inhibition is a rational target for novel therapeutic strategies in the setting of treatment-resistant breast cancer.…”

p21 in Cancer Research

“…p53-MDM2 interaction inhibitors could be used to increase p21 expression for cancer treatment. In literature, there are many inhibitors to disrupt p53-MDM2 interaction such as HDM201 [78], MI-773 [79] and RG7112 [80]. These drugs can restore expression of p53 and p21 and decrease cell viability in tumors.…”