Research ArticleCancer

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

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Science Translational Medicine  14 Aug 2019:
Vol. 11, Issue 505, eaav7171
DOI: 10.1126/scitranslmed.aav7171

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It takes two treatments to tango

Inhibitors of cyclin-dependent kinases 4 and 6, proteins involved in cell proliferation, have shown promising results in breast cancer, but their application in other tumor types has been limited by the development of resistance. Vilgelm et al. used patient-derived xenografts in mice to study the mechanisms of this resistance in melanoma. The authors identified a shortage of p21, a protein that inhibits the cell cycle, in resistant tumors and demonstrated that it can be reversed using a pharmacological intervention. The combination therapy was effective in multiple models in vivo, suggesting that it may have clinical potential.

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.

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