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

Vilgelm, Anna E. and Saleh, Nabil and Riemenschneider, Kelsie and Slesur, Lauren and Chen, Sheau-Chian and Johnston, C. Andrew and Yang, Jinming and Johnson, Douglas B. and Al-rohil, Rami Nayef and Halilovic, Ensar and Kauffmann, Rondi M. and Hooks, Mary and Kelley, Mark and Ayers, Gregory D. and Richmond, Ann (2019) MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Science Translational Medicine, 11 (505). ISSN 19466242

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.

Item Type: Article
Date Deposited: 16 Jan 2020 00:45
Last Modified: 16 Jan 2020 00:45
URI: https://oak.novartis.com/id/eprint/40302

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