Targeted degradation of MDM2 overcomes feedback regulation of p53 signaling in Merkel cell carcinoma models
Varsha Ananthapadmanabhan, Simone Bruno, Leonard Vonk, Yu-Chen Cheng, Abeba Teshager, Benjamin K. Eschle, Charles L. Howarth, Joana S. Rodrigues, Julia Schnabel, Ananya Kodali, Prafulla C. Gokhale, Rujuta Kshirsagar, Susanne B. Breitkopf, Kirti Sharma, Joao A. Paulo, Yvonne Li, Andrew D. Cherniack, Franziska Michor, Yogesh Chutake, Joyoti Dey, James A. DeCaprio
Varsha Ananthapadmanabhan, Simone Bruno, Leonard Vonk, Yu-Chen Cheng, Abeba Teshager, Benjamin K. Eschle, Charles L. Howarth, Joana S. Rodrigues, Julia Schnabel, Ananya Kodali, Prafulla C. Gokhale, Rujuta Kshirsagar, Susanne B. Breitkopf, Kirti Sharma, Joao A. Paulo, Yvonne Li, Andrew D. Cherniack, Franziska Michor, Yogesh Chutake, Joyoti Dey, James A. DeCaprio
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Research Article Cell biology Oncology

Targeted degradation of MDM2 overcomes feedback regulation of p53 signaling in Merkel cell carcinoma models

Abstract

MDM2 is transcriptionally activated by the ST-MYCL-Tip60 complex in virus-positive Merkel cell carcinoma (MCC). MDM2 suppresses p53 and is a rational therapeutic target. MDM2 inhibitors face an intrinsic limitation: p53 activation induces MDM2 transcription, creating a feedback loop that blunts inhibitor efficacy. We demonstrate that MDM2 degraders KTX-049 and KT-253 overcome this limitation by collapsing the p53/MDM2 negative feedback loop. KTX-049 was >100-fold more potent than the MDM2 inhibitor DS-3032 across WT p53 MCC cell lines, and this superior potency was quantitatively supported by mechanistic mathematical modeling. In vivo, KT-253 produced deep and durable tumor regressions, including complete responses in patient-derived xenograft models. Acquired resistance was strongly associated with acquisition of TP53 mutations, confirming on-target pathway pressure. These findings establish feedback architecture as a critical determinant of therapeutic response and position MDM2 degradation as a qualitatively distinct strategy that produces more durable pathway engagement than MDM2 inhibition, providing a preclinical rationale for prioritizing MDM2 degraders in WT TP53 MCC.

Authors

Varsha Ananthapadmanabhan, Simone Bruno, Leonard Vonk, Yu-Chen Cheng, Abeba Teshager, Benjamin K. Eschle, Charles L. Howarth, Joana S. Rodrigues, Julia Schnabel, Ananya Kodali, Prafulla C. Gokhale, Rujuta Kshirsagar, Susanne B. Breitkopf, Kirti Sharma, Joao A. Paulo, Yvonne Li, Andrew D. Cherniack, Franziska Michor, Yogesh Chutake, Joyoti Dey, James A. DeCaprio

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Figure 3

Mathematical modeling shows that KTX-049 collapses the p53/MDM2 feedback loop, making it more potent than DS-3032.

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Mathematical modeling shows that KTX-049 collapses the p53/MDM2 feedback...
(A) Diagram of the p53/MDM2 feedback loop circuit. See Supplemental Figure 6A for the reactions and ODEs associated with this diagram. (B) Diagram illustrating the effect of KTX-049 on MDM2. See Supplemental Figure 6B for the reactions and associated ODEs. (C) Diagram illustrating the effect of DS-3032 on MDM2. See Supplemental Figure 6C for the reactions and associated ODEs. (D and E) Observed experimental data (dots) and estimated trajectories (solid lines and shaded areas representing the mean and 95% credible interval [CI], respectively) of p53 and MDM2 under DMSO, 1 nM KTX-049, or 100 nM DS-3032 treatment in the MCCP MKL-1 (D) and WaGa (E) cell lines. The data used for the parameter estimation and shown in these panels correspond to those in Figure 2, A and B. (F) Validation of the conditions under which KTX-049 is more potent than DS-3032 for the data in Figure 2, A and B. More precisely, we have a = 0.049 nM–1 h–1, d = 5.75 h–1, δ = 0.92 h–1, and γ = 2.46 nM–1 h–1 for MKL-1 and a = 0.015 nM–1 h–1, d = 6.13 h–1, δ = 2.88 h–1, and γ = 1.22 nM–1 h–1 for WaGa.