Abstract
With the adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) in combination with endocrine therapy as standard of care for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer, the search is now on for novel therapeutic options to manage the disease after the inevitable development of resistance to CDK4/6i. In this review we will consider the integral role that the p53/MDM2 axis plays in the interactions between CDK4/6, ERα, and inhibitors of these molecules, the current preclinical evidence for the efficacy of MDM2 inhibitors in ER+ breast cancer, and discuss the possibility of targeting the p53/MDM2 via inhibition of MDM2 in the CDK4/6i resistance setting.
Highlights
The widespread adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer will fundamentally change the biology and natural history of a disease that effects a significant proportion of the population
Resistance to treatment is almost inevitable, either via underlying mechanisms or by the acquisition of resistant phenotypes. This leads to an urgent unmet clinical need for novel therapeutics in the CDK4/6i resistant setting; a setting that crosses multiple checkpoints and signalling pathways involved in cell cycle progression, senescence and apoptosis
Given the key role for senescence in synergy between MDM2i and cell cycle targeted therapies in ER+ breast cancer, it is possible that it is the susceptibility of a particular tumour type to senescence that is a key determinant of response to this type of combination therapy
Summary
The widespread adoption of inhibitors of cyclin dependent kinases 4 and 6 (CDK4/6i) for the treatment of advanced and metastatic estrogen receptor positive (ER+) breast cancer will fundamentally change the biology and natural history of a disease that effects a significant proportion of the population. Given the key role for senescence in synergy between MDM2i and cell cycle targeted therapies in ER+ breast cancer, it is possible that it is the susceptibility of a particular tumour type to senescence that is a key determinant of response to this type of combination therapy In support of this hypothesis, a recent study that used the combination of MDM2i and CDK4/6i in patient derived models of melanoma with insensitivity or resistance to CDK4/6i [70], did report a synergistic response and identified increased cell cycle arrest and gene expression changes consistent with senescence in combination treated samples. In contrast with the modest clinical response seen in solid tumours, idasanutlin in AML demonstrated significant responses as both monotherapy and in combination with cytarabine chemotherapy, with a composite complete
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