mercaptopurine and lometrexol

Patients with relapsed/refractory Burkitt's lymphoma (BL) have a dismal prognosis. Current research efforts aim to increase cure rates by identifying high-risk patients in need of more intensive or novel therapy. The 8q24 chromosomal translocation of the c-Myc gene, a main molecular marker of BL, is related to the metabolism by regulating phosphoribosyl pyrophosphate synthetase 2 (PRPS2). In our study, BL showed significant resistance to thiopurines. PRPS2 homologous isoenzyme, PRPS1, was demonstrated to play the main role in thiopurine resistance. c-Myc did not have direct effects on thiopurine resistance in BL for only driving PRPS2. PRPS1 wild type (WT) showed different resistance to 6-mercaptopurine (6-mp) in different metabolic cells because it could be inhibited by adenosine diphosphate or guanosine diphosphate negative feedback. PRPS1 A190T mutant could dramatically increase thiopurine resistance in BL. The interim analysis of the Treatment Regimen for Children or Adolescent with mature B cell non-Hodgkin's lymphoma in China (CCCG-B-NHL-2015 study) confirms the value of high-dose methotrexate (MTX) and cytarabine (ARA-C) in high-risk paediatric patients with BL. However, there remains a subgroup of patients with lactate dehydrogenase higher than four times of the normal value (4N) for whom novel treatments are needed. Notably, we found that the combination of thiopurines and the phosphoribosylglycinamide formyltransferase (GART) inhibitor lometrexol could serve as a therapeutic strategy to overcome thiopurine resistance in BL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Burkitt Lymphoma; Cell Line, Tumor; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Mercaptopurine; Mutation; Nucleotides; Proto-Oncogene Proteins c-myc; Ribose-Phosphate Pyrophosphokinase; Tetrahydrofolates

Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL.

Topics: Adolescent; Child; Child, Preschool; Exome; Feedback, Physiological; Female; High-Throughput Nucleotide Sequencing; Humans; Infant; Leukemia, B-Cell; Male; Mercaptopurine; Mutation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Purines; Recurrence; Ribose-Phosphate Pyrophosphokinase; Tetrahydrofolates