Here, we assess how HSF1 activation influences mutational trajectories by which p53 can escape cytotoxic pressure from nutlin-3, an inhibitor of the p53 regulator mouse double minute 2 homolog (MDM2). HSF1 activation broadly increases the fitness of dominant-negative p53 substitutions, particularly non-conservative, biophysically unfavorable amino acid changes within buried regions of the p53 DNA-binding domain. These findings demonstrate that HSF1 activation reshapes the oncogenic mutational landscape by preferentially supporting the emergence and persistence of biophysically disruptive, cancer-associated p53 substitutions, linking proteostasis network activity directly to oncogenic evolution.

To investigate whether MDM2 can serve as tumor-specific PROTAC E3 in certain setting, we analyzed the benchmark compound A1874 (JQ1-Idasanutlin chimera targeting BRD4) under various conditions that affect MDM2 expression and activity. Importantly, A1874 showed on average ~12-fold higher potency in tumor cells with MDM2 amplification compared to non-amplified cells, correlating with enhanced cytotoxicity. The results suggest that tumors with MDM2 amplification or overexpression can be selectively targeted using PROTAC approach.

GSDME-mediated pyroptosis plays a pivotal role in chemotherapy-induced cell death in lung adenocarcinoma. MDM2 inhibition, which switches pyroptosis to apoptosis, can be employed to regulate chemotherapy-induced pyroptosis in lung cancer cells and normal tissue cells.

To address these challenges, we developed a novel nanotherapeutic platform (FAB) that integrated γ-Fe2O3 nanoparticles with the MDM2-p53 inhibitor APG-115, sensitizing tumor to therapy via targeting p53/SLC7A11 axis to bidirectionally regulate ferroptosis and induce cell senescence...Notably, senescent tumor cells exhibit increased thermal susceptibility under AMF, ultimately leading to selective apoptosis. Our study not only elucidated the crosstalk between p53 activation and ferroptosis facilitation in mediating senescence but also provided a promising strategy for enhanced tumor treatment.

In mutant p53 cells, combination therapy may provide partial benefits. These findings support ALRN-6924 clinical development as targeted therapy for p53-functional CLL, particularly in combination strategies.

In addition, Nutlin-3 treatment decreased the EDmax value in p53 wild-type U2OS cells from 0.43 to 0.20. In summary, our method can identify p53-MDM2 interaction inhibitors in living cells, providing a quantitative in vivo supplement for traditional target-based drug discovery.

High doses of idasanutlin decreased the proliferation of T cells and depleted T cell numbers within the lymphocyte population, as we show in vitro and in vivo. These findings suggest that low doses of MDM2 antagonists may enhance immunotherapy, while higher doses could interfere with immunotherapy by p53-mediated cell cycle arrest and decreasing the proliferation of the immune cells.

Keap1-based degraders eliminate oncogenic KRAS and androgen receptor in cancer, antifolate-idasanutlin hybrids degrade Plasmodium falciparum DHFR-TS to overcome antifolate resistance, and PLK1 inhibition suppresses NLRP3 inflammasome activation to improve cardiac outcomes. Together, these innovations expand degrader and kinase-targeting strategies into oncology, infectious disease, and inflammatory cardiology.

The efficacy of the mouse double minute 2 homolog (MDM2) inhibitor (HDM201) and the Wee1 G2 checkpoint kinase (Wee1) inhibitor (adavosertib) was confirmed in both p53 wild-type (p53 WT) and p53 mutant (p53 MT) GIST cells. Our results highlight the importance of p53 status in guiding GIST treatment. p53 WT tumors respond to MDM2 inhibitors, while p53 MT tumors show greater sensitivity to Wee1 inhibitors, supporting p53 pathway targeting as a promising strategy for GIST patients.

Short hairpin RNA-mediated MDM2 knockdown and the p53-MDM2 inhibitors, nutlin-3 and RG7388, induced apoptosis in TP53_WT GC cells, indicating that activated MDM2 suppressed p53 protein levels and thereby attenuated the downstream p53 pathway activation, which was restored upon MDM2 knockdown or inhibitor treatment. Collectively, DNA-hypermethylated GC cases, HME_MLH1(-)/MSI and E-HME/EBV, follow a unique carcinogenic pathway to evade apoptosis in the absence of TP53 mutation, potentially making them responsive to therapeutic strategies that function primarily through the p53 pathway.

P1, N=35, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jul 2025 --> Jul 2027 | Trial primary completion date: Jul 2025 --> Jul 2027

P1, N=39, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed | Trial completion date: Feb 2026 --> Sep 2025