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

Publication ,  Journal Article
Vilgelm, AE; Saleh, N; Shattuck-Brandt, R; Riemenschneider, K; Slesur, L; Chen, S-C; Johnson, CA; Yang, J; Blevins, A; Yan, C; Johnson, DB ...
Published in: Sci Transl Med
August 14, 2019

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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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

August 14, 2019

Volume

11

Issue

505

Location

United States

Related Subject Headings

  • Radioimmunoprecipitation Assay
  • Proto-Oncogene Proteins c-mdm2
  • Proteomics
  • Mice, Nude
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Melanoma
  • MCF-7 Cells
  • Immunoprecipitation
 

Citation

APA
Chicago
ICMJE
MLA
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Vilgelm, A. E., Saleh, N., Shattuck-Brandt, R., Riemenschneider, K., Slesur, L., Chen, S.-C., … Richmond, A. (2019). MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Sci Transl Med, 11(505). https://doi.org/10.1126/scitranslmed.aav7171
Vilgelm, Anna E., Nabil Saleh, Rebecca Shattuck-Brandt, Kelsie Riemenschneider, Lauren Slesur, Sheau-Chiann Chen, C Andrew Johnson, et al. “MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.Sci Transl Med 11, no. 505 (August 14, 2019). https://doi.org/10.1126/scitranslmed.aav7171.
Vilgelm AE, Saleh N, Shattuck-Brandt R, Riemenschneider K, Slesur L, Chen S-C, et al. MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Sci Transl Med. 2019 Aug 14;11(505).
Vilgelm, Anna E., et al. “MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.Sci Transl Med, vol. 11, no. 505, Aug. 2019. Pubmed, doi:10.1126/scitranslmed.aav7171.
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. MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Sci Transl Med. 2019 Aug 14;11(505).

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

August 14, 2019

Volume

11

Issue

505

Location

United States

Related Subject Headings

  • Radioimmunoprecipitation Assay
  • Proto-Oncogene Proteins c-mdm2
  • Proteomics
  • Mice, Nude
  • Mice, Inbred C57BL
  • Mice, Inbred BALB C
  • Mice
  • Melanoma
  • MCF-7 Cells
  • Immunoprecipitation