Vilgelm, Anna E., Saleh, Nabil, Riemenschneider, Kelsie, Slesur, Lauren, Chen, Sheau-Chian, Johnston, C. Andrew, Yang, Jinming, Johnson, Douglas B., Al-rohil, Rami Nayef, Halilovic, Ensar, Kauffmann, Rondi M., Hooks, Mary, Kelley, Mark, 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