DTcP

Several studies reported that drug therapy problems (DTPs) were prevalent in cancer patients. These DTPs are still interfering with the desired treatment outcomes in patients with cancer. This study aimed to determine the prevalence, types and predictors of DTPs among paediatric acute lymphoblastic leukaemia (ALL) patients at Kenyatta National Hospital.

A retrospective cohort study was used to assess DTPs among ALL patients. Records of all eligible paediatric patients with ALL who received treatment in the facility between 1 January 2017 and 31 December 2021 were examined. A data abstraction tool was employed for data collection. The data entry and analysis were carried out by a statistical package for social sciences version 29.0 software. Frequency tables were utilised to present the key findings of the study. Binary logistic regression analysis was utilised to determine the predictors of DTPs.

A total of 82 DTPs were identified with the most common type of DTP being adverse drug reaction (ADR; 59, 72.0%) and drug interaction (9, 11.0%). The most common ADRs identified were febrile neutropenia (20, 33.9%), nausea/vomiting (14, 23.7%) and anaemia (11, 18.6%). Patients with central nervous system disease (adjusted odds ratio [AOR] = 10.2, 95% CI = 1.2–85.8, p  = 0.03) and treated with a combination of chemotherapy and radiotherapy (AOR = 13.5, 95% CI = 1.9–89.4, p  = 0.01) were more likely to develop DTPs.

The study found that the prevalence of DTPs among paediatric ALL patients was high, with the most common DTPs being ADRs occurring in 72.0% of patients. Central nervous system metastasis and a combination of chemotherapy and radiation treatment regimens were statistically significant predictors of DTPs.

The generation of drug-tolerant persister (DTP) cancer cells remains a major challenge for lung adenocarcinoma (LUAD) patients treated with EGFR-tyrosine kinase inhibitors (TKIs), as these cells eventually lead to drug resistance and disease progression. However, the mechanisms underlying DTP formation are poorly understood, limiting treatment options when DTP state or resistance emerges following TKI therapy. In this study, utilizing samples from LUAD patients receiving front-line osimertinib therapy, including baseline, DTP, and stable resistance states, we dissected the cellular and transcriptomic features of TKI-induced DTP cells. These cells exhibited an active drug-metabolizing phenotype, characterized by significantly increased expression of Glutathione S-Transferase Alpha 1 (GSTA1), which was regulated by Radial Spoke Head Component 1 (RSPH1). Mechanistically, we demonstrated that elevated GSTA1 expression in cancer cells promoted osimertinib degradation. Furthermore, RSPH1+ DTP cells interacted with macrophages via Protein S (PROS1)-AXL signaling to establish an immunosuppressive tumor microenvironment (TME), thereby contributing to persister formation. We investigated the RSPH1-CALML4-GSTA1 regulatory axis and found that PROS1 expression was also governed by this axis, suggesting that GSTA1 acted as an upstream regulator of the PROS1-AXL signaling pathway. We evaluated the feasibility of combination therapy using osimertinib and the GSTA1 inhibitor curzerene in both osimertinib-induced DTP and acquired resistance mouse models. Notably, this strategy demonstrated superior efficacy and safety compared to chemotherapy or AXL inhibitor combination in both settings. Collectively, our study elucidated novel mechanisms contributing to the TKI-induced DTP state and provided a promising combination strategy to overcome drug tolerance and resistance in osimertinib-treated LUAD patients.