Although substantial evidence supports the association between UGT1A1 genotype and drug safety, implementation of genotype-guided treatment remains inconsistent, and further harmonization of international recommendations, high-quality prospective studies, and wider access to pharmacogenetic testing are needed to support routine implementation.
Abstract
Pharmacogenetics has transformed oncology by enabling personalized, effective and safer use of anticancer therapies. Among clinically relevant pharmacogenetic biomarkers, polymorphisms in the UGT1A1 gene influence the metabolism of irinotecan and other SN-38-based agents, increasing the risk of treatment-related toxicities. Beyond SN-38-based therapies, UGT1A1 contributes to the metabolism of endogenous compounds and several drugs, and its activity may be affected by concomitant inhibitors or inducers, highlighting its broader clinical relevance. Although substantial evidence supports the association between UGT1A1 genotype and drug safety, implementation of genotype-guided treatment remains inconsistent. This narrative review summarizes the biological basis and clinical relevance of UGT1A1 polymorphisms in patients receiving SN-38-based therapies. Original studies, systematic reviews, meta-analyses, and international and regional pharmacogenetic guidelines were evaluated regarding genotype-guided dosing, clinical outcomes, implementation strategies, and barriers to routine testing. Reduced-function UGT1A1 variants are associated with increased risk of irinotecan-induced neutropenia and diarrhea, particularly at higher doses. However, recommendations from scientific societies differ regarding testing indications, dose adjustment strategies, and patient selection. Uncertainties remain concerning the clinical implications of UGT1A1 variability for newer antibody–drug conjugates carrying an SN-38 payload. Practical barriers, including inconsistent guideline recommendations, limited access to testing, reimbursement issues, and heterogeneous clinical workflows, continue to restrict implementation. UGT1A1 genotyping represents a valuable tool for improving the safety of selected anticancer therapies, yet its incorporation into clinical practice remains incomplete. As precision oncology evolves, pharmacogenetic testing may optimize treatment selection, reduce toxicity, and improve outcomes. Further harmonization of international recommendations, high-quality prospective studies, and wider access to pharmacogenetic testing are needed to support routine implementation.
Interpatient variability in chemotherapy response and toxicity remains a major challenge in oncology. Pharmacogenomics (PGx) is an approach to address this challenge by combining somatic alterations that affect tumour sensitivity with germline variants that affect drug metabolism, transport and toxicity. This review provides a critical evaluation of clinically validated PGx biomarkers for chemotherapeutics and targeted therapy with a focus on translational relevance and strength of evidence. High-impact germline markers such as DPYD, TPMT, NUDT15 and UGT1A1 are highlighted as key determinants of genotype-guided dosing for improving safety without compromising efficacy. Somatic biomarkers such as EGFR, RAS, BRAF, and HER2 remain central to treatment selection, while resistance underscores the need for ongoing molecular assessment. A tiered implementation framework, barriers to progress, and future directions involving polygenic models, multi-omics, and artificial intelligence (AI) are discussed to advance safe, effective, and personalized chemotherapy.
Satyam Kumar Vishwash, Ram Babu Soni, Sourabh Kosey et al.· Journal of chemotherapy· 0 citations
Cardio-oncology patients may face complex treatment regimens due to the concurrent existence of cancer and cardiovascular disease, leading to a considerable polypharmacy burden. This significantly increases the prospect of drug-drug interactions (DDIs) and gene-drug interactions. The majority of these interactions arise from comparable pharmacokinetic and pharmacological pathways associated with drug transporters and cytochrome P450 enzymes. The significance of pharmacogenomics in tailored treatment strategies are emphasised by the fact that genetic variability enhances individual differences in drug response, safety, and efficacy. This narrative review focus on the effects of key genetic polymorphisms (e.g., DPYD, CYP2C19, and CYP2C9) on the metabolism and efficacy of commonly prescribed anticancer and cardiovascular medications such as fluoropyrimidines, clopidogrel, and warfarin. In addition it explore the role of pharmacogenomic variants on drug-drug interactions within the field of cardio-oncology. The study ultimately emphasizes the necessity of precision medicine in India to address the genetic diversity and underrepresentation in global genomic databases. The absence of pharmacogenomic testing, infrastructural deficiencies, financial constraints, and insufficient clinical integration hinder the widespread use of this technology in India. The Genome India Project and other national initiatives establish the foundation for pharmacogenomic-guided therapy. Utilizing genetic data, together with artificial intelligence-based predictive tools, for clinical decision-making may enhance medication safety and yield optimal outcomes in Indian cardio-oncology patients.
Aanya Verma, P. D.· Current problems in cardiolo...· 0 citations
The integration of pharmacogenomics into routine healthcare has the potential to optimize individualized drug therapy, minimize preventable ADRs, and accelerate the transition toward precision medicine, ultimately improving clinical outcomes and healthcare quality.
Rayapudi Vasavi Sai Saraswati, U. M. Vattikuti, Arthika Chauhan Laudia et al.· International Journal of Cur...· 0 citations
Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting toxicity of cancer treatment, yet reliable biomarkers to predict individual susceptibility remain lacking. Germline genetic variation has been widely investigated as a potential contributor to CIPN risk; however, the consistency and clinical utility of these associations remain unclear. We performed a systematic review of genetic association studies evaluating CIPN across neurotoxic chemotherapies. PubMed, Embase, Web of Science, and the Cochrane Library were searched (April 2025) for human studies assessing germline variants in relation to clinician- or patient-reported CIPN. Eligible studies were identified in four major drug classes: vincristine, taxanes, platinum agents, and bortezomib. Study characteristics, phenotyping approaches, ancestry, and variant-level data were extracted, and study quality was assessed using Q-Genie. Meta-analysis was not performed due to substantial heterogeneity in study design and outcome measures. 72 studies were included, predominantly involving cohorts of European ancestry. The most consistently replicated loci were CEP72 and ETAA1 for vincristine-induced neuropathy; EPHA5, FGD4, and FZD3 for taxane-induced neuropathy; and ABC transporter genes and GSTP1 for platinum-induced neuropathy. For bortezomib, associations involving TRPV1, DNA repair pathways, and inflammatory signalling showed emerging but largely non-replicated evidence. Across studies, marked heterogeneity in CIPN definitions, phenotyping instruments, statistical approaches, and effect allele reporting limited comparability and reproducibility. Collectively, these findings indicate that current pharmacogenomic approaches to CIPN are constrained by poor replication, population bias, and inconsistent methodology, which hinder translation into clinically actionable biomarkers. Future progress will require harmonised phenotyping, multi-ancestry genome-wide studies, and integration of functional validation to enable robust risk stratification and precision oncology approaches to CIPN. Systematic Review Registration Identifier PROSPERO [CRD42025635757].
Aditya Maganti, Ishara Rankothge, Hunter Sakadales et al.· Frontiers in Pharmacology· 1 citation
The integration of artificial intelligence and machine learning approaches for pharmacogenomic prediction, the emergence of polygenic risk scores, and the role of multi-omics integration in refining therapeutic decision-making are examined.
Hao Sun, Zijun Qiao, Jinze Yu et al.· Brazilian Journal of Science· 0 citations
Background/Objectives: Colorectal cancer (CRC) remains a leading cause of cancer-associated mortality worldwide. The current therapeutic interventions are heavily constrained by the development of resistance and severe systemic toxicity. To address these challenges, this study integrated a multi-disciplinary framework involving high-throughput in silico screening followed by in vitro experimental validation to identify novel genetic targets of CRC and evaluate the efficacy of FDA-approved drugs. The primary objective was to identify safe and selective therapeutic agents capable of modulating their effect. Methods: The methodology employed a systematic screening of recent large-scale Genome-Wide Association Studies (GWASs) to pinpoint novel targets, followed by in silico pathogenicity prediction, homology modelling and high-throughput virtual screening of over 1615 FDA-approved drugs. The prioritized candidates were validated in vitro using MTT cytotoxicity assays and differential gene expression analysis across CRC cell lines (HCT116 and HT29) and a non-tumorigenic control, Human embryonic kidney cell line HEK293. Results: In silico analysis identified CLUH, CLSTN3 and SLC11A2 as novel potential targets. Based on in silico predicted deleterious mutations and subsequent molecular docking-based virtual screening, Telmisartan, Dutasteride and Venetoclax were prioritized. This prioritization was supported by their high binding affinity and dose-dependent cytotoxicity in MTT assays; thus, suggesting their repurposing potential for CRC treatment. Telmisartan exhibited a superior therapeutic profile not only in terms of the statistically significant cytotoxicity (p < 0.01), but also its selective effect on HCT116 and HT29 when compared to high safety profile in HEK293. This was further validated when Telmisartan selectively downregulated CLUH and SLC11A2 in CRC cell lines, HCT116 and HT29 while maintaining expression levels in the non-cancerous HEK293 cell line remained significantly unaffected. Furthermore, a 100 ns molecular dynamics simulation confirmed the stable binding conformation and structural reliability of the SLC11A2 (Trp179Ser)–Telmisartan complex. Conclucions: Our findings conclude that Telmisartan is a promising candidate for drug repurposing for CRC treatment and capable of modulating selected novel biomarkers CLUH and SLC11A2. However, further multi-omics-based confirmatory studies and pre-clinical validation studies are needed in the future to confirm the long-term efficacy of this repositioning strategy.
Sarah Hunachagi, H. H. Alqudihi, S. Abdulazeez et al.· Pharmaceutics· 0 citations