Pharmacogenomic and mechanistic analysis of genetic predisposition to l-asparaginase-induced pancreatitis in pediatric patients with cancer
Year: 2026
Type: dissertation
Study design: Observational Study
Abstract: L-asparaginase is a critical component in treatment protocols for pediatric acute lymphoblastic leukemia. Acute pancreatitis reactions can necessitate delays, and in severe cases, discontinuation of l-asparaginase, which severely compromise clinical outcomes. Although genetic biomarkers for l-asparaginase-induced pancreatitis have been investigated, there has been limited replication of these associations and understanding of the mechanistic basis underlying this adverse drug reaction. Case-control genome-wide analyses were conducted to identify significant associations between single nucleotide polymorphisms and risk for l-asparaginase-induced pancreatitis in 1,086 pediatric patients treated on acute lymphoblastic leukemia treatment protocols. Patients were randomly split 75/25 into independent Discovery (n = 824) and Replication (n = 262) cohorts. A significant association was observed between the rs149210846 variant and l-asparaginase-induced pancreatitis (odds ratio [OR] = 8.9; 95% confidence interval [CI]: 3.6 – 22.3; P = 1.8x10⁻⁸) and was confirmed in the replication analysis (OR = 6.2; 95% CI: 1.1 – 35.0; P = 0.02). Carriers had 5.9-fold (95% CI: 1.9 – 16.3; P = 0.002) and 7.7-fold (96% CI: 1.3 – 29.3; P = 0.01) increased risk for severe Grade 3 and Grade 4 acute pancreatitis reactions, respectively. Admixed-American ancestry is a reported risk factor for l-asparaginase-induced pancreatitis. Interestingly, patients of Admixed-American (OR = 9.0; 95% CI: 2.2 – 39.0; P = 0.002) and Asian (OR = 10.4; 95% CI: 2.9 – 43.7; P = 5.0x10-4) genetic ancestries in this study were at significantly higher risk. The rs149210846 variant is in a regulatory region of PKR. In a rat pancreatic AR42J cell model, PKR knockdown significantly reduced l-asparaginase-induced cytotoxicity compared to controls (P = 0.008). Importantly, there was a 1.7-fold increase in autophagic flux observed in PKR knockdown cells treated with l-asparaginase compared to unexposed control (P = 0.02), suggesting an adaptive response associated with reduced PKR activity. Pharmacologic inhibition of PKR using C16 recapitulated these findings and attenuated cytotoxicity across a range of l-asparaginase concentrations. Together, these pharmacogenomic and functional data bridge the gap between discovery and clinical implementation. These findings allow clinicians to proactively conduct stricter monitoring of patients predisposed to l-asparaginase-induced pancreatitis and inform development of protective agents that can be used concomitantly to mitigate their risk.
DOI: 10.14288/1.0456104
Author: Raack, Edward James
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7212257707