CDK4 inhibition diminishes p53 activation by MDM2 antagonists

Abstract

The genes encoding MDM2 and CDK4 are frequently co-amplified in sarcomas, and inhibitors to both targets are approved or clinically tested for therapy. However, we show that inhibitors of MDM2 and CDK4 antagonize each other in their cytotoxicity towards sarcoma cells. CDK4 inhibition attenuates the induction of p53-responsive genes upon MDM2 inhibition. Moreover, the p53 response was also attenuated when co-depleting MDM2 and CDK4 with siRNA, compared to MDM2 single knockdown. The complexes of p53 and MDM2, as well as CDK4 and Cyclin D1, physically associated with each other, suggesting direct regulation of p53 by CDK4. Interestingly, CDK4 inhibition did not reduce p53 binding or histone acetylation at promoters, but rather attenuated the subsequent recruitment of RNA Polymerase II. Taken together, our results suggest that caution must be used when considering combined CDK4 and MDM2 inhibition for patient treatment. Moreover, they uncover a hitherto unknown role for CDK4 and Cyclin D1 in sustaining p53 activity.

Combined targeting of the p53 and pRb pathway in neuroblastoma does not lead to synergistic responses

“…Synergistic effects were obtained in neuroblastoma by combining nutlin-3 (an older generation MDM2 inhibitor) with the pan-CDK inhibitor seliciclib [40], possibly via the inhibition of CDK2 and CDK9, as well as in liposarcoma and melanoma by combining MDM2 inhibition with palbociclib [41,42]. On the contrary, an antagonistic effect was found in sarcoma cells [43]. The two inhibited pathways are interconnected in several ways, which could explain the absence of synergism.…”

“…The two inhibited pathways are interconnected in several ways, which could explain the absence of synergism. Sriraman et al found that the CDK4-cyclin D1 complex can bind to p53, which is essential for transcription of p53 target genes [43]. CDK4/6 inhibitors might block this interaction and counteract the effect of MDM2 inhibition.…”

Functional genomics identifies predictive markers and clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer

“…Development of novel inhibitors might allow improvement of combination therapies with CDK4/6 inhibitors by characterizing those pathways in greater detail. The diversity of different signaling events involved in the cellular response to CDK4/6 inhibitors reflect probably the diverse and complicated downstream signaling network of CDK4/6 as described only recently [20, 51, 52]. This diversity of molecular candidates that confer resistance might also explain why the identification of single reliable predictive markers was not successful in clinical trials to date.…”

A review of retroperitoneal liposarcoma genomics

“…However, recently Sriraman et al have disputed this synergistic concept after finding that MDM2 and CDK4 inhibitors can antagonise each other in their cytotoxicity. They found nutlin treated liposarcoma cells survived longer when co-treated with palbocicib concluding that CDK4 is required for p53 induced-gene expression [48].…”