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MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21
Anna E Vilgelm1,2,3, Nabil Saleh4,2, Rebecca Shattuck-Brandt4,2
1Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN 37212, USA. vilgelm.1@osu.edu.
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.
Insights
Researchers found that combining CDK4/6 inhibitors with MDM2 antagonists can overcome resistance in melanoma. This strategy stabilizes p53, increasing p21 levels and restoring sensitivity to CDK4/6 inhibitors for improved tumor regression.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) show limited efficacy in melanomas due to intrinsic resistance.
- The mechanisms underlying CDK4/6i resistance in melanoma are not fully understood, hindering broader clinical application.
Purpose of the Study:
- To investigate the mechanisms of CDK4/6i resistance in melanoma using patient-derived xenografts (PDXs).
- To identify therapeutic strategies to overcome CDK4/6i resistance and improve treatment outcomes in melanoma.
Main Methods:
- Utilized melanoma patient-derived xenografts (PDXs) to model CDK4/6 inhibitor resistance.
- Investigated the role of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway and p21 in mediating resistance.
- Co-administered CDK4/6 inhibitors with a murine double minute (MDM2) antagonist to stabilize p53 and induce p21.
- Evaluated antitumor activity in PDXs and murine melanoma models.
- Employed an ex vivo organotypic slice culture assay for potential patient stratification.
Main Results:
- Melanoma PDXs resistant to CDK4/6i exhibited activation of the PI3K-AKT pathway.
- Inhibition of the PI3K-AKT pathway restored sensitivity to CDK4/6i in a p21-dependent manner.
- Upregulation of cyclin D1 by CDK4/6i sequestered p21 and p27, inhibiting CDK2.
- Co-administration of CDK4/6 and MDM2 antagonists led to p21 accumulation, enhanced antitumor activity, and tumor regression.
- Molecular features of response in PDXs were mirrored in ex vivo organotypic slice cultures.
Conclusions:
- Activation of the PI3K-AKT pathway and subsequent p21 sequestration contribute to CDK4/6i resistance in melanoma.
- Cotargeting CDK4/6 and MDM2 by stabilizing p53 to induce p21 is a promising strategy to overcome resistance.
- Combination therapy with CDK4/6 and MDM2 antagonists, potentially with standard care, can induce tumor regression in melanoma.
- Ex vivo organotypic slice culture assays may aid in patient stratification for this combination therapy.
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