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

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.

Targeting dual signaling pathways in concert with immune checkpoints for the treatment of pancreatic cancer

“…To determine the features of therapeutic cooperation, we interrogated canonical determinants of cell cycle control. Treatment with CDK4/6 inhibitors lead to the adaptive upregulation of cyclin D1 and cyclin E in the pancreatic cancer cell lines (Fig 1D), consistent with prior findings 37, 38 . These adaptive features of CDK4/6 inhibition were ameliorated with the combined treatment with trametinib that yielded potent blockade of RB phosphorylation and suppression of cyclin A expression (Fig 1D).…”

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

“…The protein p21 CIP was characterized as a CDK inhibitor at high p21 protein levels. 74 Although it has been discovered, that MDM2i synergistically work with CDK4/6i, 75 direct effects on the CDK4/6 protein levels have not been described yet. To shed light on the underlying mechanism, we investigated if CDK4/6 degradation is directly proportional to p53/p21 levels.…”

Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway

“…Cyclin D1, a member of the cyclin family (D1, D2, and D3) which functions as a regulatory subunit and forms a complex with CDK4 or CDK6 for regulating cell cycle transition from the G 1 to S phase [26], is frequently overexpressed in cancer cells and dysregulates CDK activity. P21 and P27 have been reported as classic CDKIs, and negatively correlated with CDK4/6 and cyclin D1 expression [27,28]. In tumor cells, overexpression of cyclin D1 and down-regulation or dysfunction of its negative regulatory proteins P21 and P27 are very common, these changes are closely related to the abnormal proliferation of tumors.…”