MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Vilgelm, AE; Saleh, N; Shattuck-Brandt, R; Riemenschneider, K; Slesur, L; Chen, S-C; Johnson, CA; Yang, J; Blevins, A; Yan, C; Johnson, DB; Al-Rohil, RN; Halilovic, E; Kauffmann, RM; Kelley, M; Ayers, GD; Richmond, A
Published Date
- August 14, 2019
Published In
Volume / Issue
- 11 / 505
PubMed ID
- 31413145
Pubmed Central ID
- PMC7584132
Electronic International Standard Serial Number (EISSN)
- 1946-6242
Digital Object Identifier (DOI)
- 10.1126/scitranslmed.aav7171
Language
- eng
Conference Location
- United States