Targeting the MDM2-p53 Interaction with Siremadlin: A Promising Therapeutic Strategy for Treating TP53 Wild-Type Chronic Lymphocytic Leukemia

<b>Background:</b> Chronic lymphocytic leukemia (CLL) treatment has transitioned from traditional chemotherapy to more targeted therapies, but challenges such as resistance and suboptimal responses persist. This study aimed to evaluate HDM201, a second-generation MDM2-p53 binding antagonist, as a novel therapeutic strategy for CLL, with a focus on its effectiveness across different <i>TP53</i> genetic contexts. <b>Methods:</b> We utilized a panel of B cell leukemia-derived cell lines with varying <i>TP53</i> statuses, including <i>TP53</i>-knockout (KO) derivatives of the human B cell line Nalm-6, and assessed the impact of HDM201 on primary CLL samples with both <i>TP53</i> wild-type and mutant backgrounds. <b>Results:</b> Our results revealed that <i>TP53</i> wild-type and heterozygous <i>TP53</i>-KO Nalm-6 cells were sensitive to HDM201, whereas homozygous <i>TP53</i>-KO cells and B cells with <i>TP53</i> mutations exhibited significant resistance. Resistance was also noted in primary CLL samples with <i>TP53</i> mutations. HDM201 effectively stabilized p53 and induced apoptosis in <i>TP53</i> wild-type cells but had limited efficacy in <i>TP53</i> mutant cells. <b>Conclusions:</b> These findings indicate that HDM201 holds promise as an additional targeted therapy option for wild-type <i>TP53</i> CLL. The results underline the importance of <i>TP53</i> status in predicting treatment efficacy and highlight the potential of HDM201 as a valuable addition to explore in CLL therapy. Future research should focus on identifying additional biomarkers of response and exploring the optimal way to include HDM201 in combination therapies to improve treatment outcomes in CLL.