Investigating mechanisms of resistance to serdemetan in neuroblastoma

Neuroblastoma is the most abundant extra-cranial tumor in pediatric patients. Though outlook for low-risk patients has significantly improved in the last decade, those classified as high-risk face uncertain outcomes. Drug-resistance is the principal issue, causing relapse and death for approximately 50% of high-risk patients. MDM2 inhibitors are under investigation as drug candidates for neuroblastoma. They induce p53 anticarcinogenic activity by disrupting the negative feedback interaction between MDM2 and p53, and are known to induce TP53 mutations as a resistance mechanism. Serdemetan, introduced as an MDM2 inhibitor, is one such drug where the likelihood of resistance development is high. Therefore it serves as a useful model for studying resistance formation. Investigation into how resistance develops is critical to circumnavigating it and improving high-risk patient survival rates. To address this, exome data from serdemetan-adapted sublines of the neuroblastoma cell line UKF-NB-3 were compared to those derived from the parental UKF-NB-3 cell line. Critical variants and pathways effected were identified and the degree of similarity between the sublines was established. Sublines containing TP53 null mutations were found to contain a high degree of similarity in variants acquired after serdemetan treatment, while those wild type for this gene were more similar. Three pathways were determined to be critically mutated, with alterations likely leading to resistance formation: 1) the cholesterol transport pathway, 2) the p53 signaling pathway, and 3) the xenobiotic clearance pathway. The involvement of multiple pathways indicates that there is not a one-size-fits-all mechanism of action through which resistance to serdemetan develops. However, mutations to the cholesterol transport pathway were deemed to be the most crucial to resistance formation, as the presence of these alone were enough to induce it. These findings implicate the cholesterol transport pathway in serdemetan's mechanism of action, confirming its' mechanisms exist beyond just modulation of MDM2 activity.