MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.

Abstract

Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.

• Authors: Anna E Vilgelm, Nabil Saleh, Rebecca Shattuck-Brandt, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chiann Chen, C Andrew Johnson, Jinming Yang, Ashlyn Blevins, Chi Yan, Douglas B Johnson, Rami N Al-Rohil, Ensar Halilovic, Rondi M Kauffmann, Mark Kelley, Gregory D Ayers, Ann Richmond
• Journal: Science translational medicine (Sci Transl Med) Vol. 11 Issue 505 (08 14 2019) ISSN: 1946-6242 [Electronic] United States
• PMID: 31413145 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• Proto-Oncogene Proteins c-mdm2
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• Dimethyl Sulfoxide

Topics

• Analysis of Variance
• Animals
• Blotting, Western
• Cell Cycle (drug effects)
• Cell Survival (drug effects, genetics)
• Cyclin-Dependent Kinase 4 (genetics, metabolism)
• Cyclin-Dependent Kinase 6 (genetics, metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• DNA Replication (drug effects, genetics)
• Dimethyl Sulfoxide (pharmacology)
• Humans
• Immunoprecipitation
• MCF-7 Cells
• Melanoma (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Proteomics
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors, metabolism)
• Radioimmunoprecipitation Assay