From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis
Introduction: The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has facilitated the development of precision oncology. Two first-generation NTRK inhibitors (larotrectinib and entrectinib) are currently approved for the treatment of patients with solid tumors harboring NTRK g...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2024-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2024.1329409/full |
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| author | Zhiwei Cui Zhen Zhai De Xie Lihui Wang Feiyan Cheng Siyu Lou Fan Zou Rumeng Pan Shixue Chang Haoyan Yao Jing She Yidan Zhang Xinyuan Yang |
| author_facet | Zhiwei Cui Zhen Zhai De Xie Lihui Wang Feiyan Cheng Siyu Lou Fan Zou Rumeng Pan Shixue Chang Haoyan Yao Jing She Yidan Zhang Xinyuan Yang |
| author_sort | Zhiwei Cui |
| collection | DOAJ |
| description | Introduction: The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has facilitated the development of precision oncology. Two first-generation NTRK inhibitors (larotrectinib and entrectinib) are currently approved for the treatment of patients with solid tumors harboring NTRK gene fusions. Nevertheless, comprehensive NTRK profiling at the pan-cancer genomic level and real-world studies pertaining to the adverse events of NTRK inhibitors are lacking.Methods: We characterize the genome of NTRK at the pan-cancer level through multi-omics databases such as The Cancer Genome Atlas (TCGA). Through the FDA Adverse Event Reporting System (FAERS) database, we collect reports of entrectinib and larotrectinib-induced adverse events and perform a pharmacovigilance analysis using various disproportionality methods.Results:NTRK1/2/3 expression is lower in most tumor tissues, while they have higher methylation levels. NTRK gene expression has prognostic value in some cancer types, such as breast invasive carcinoma (BRCA). The cancer type with highest NTRK alteration frequency is skin cutaneous melanoma (SKCM) (31.98%). Thyroid carcinoma (THCA) has the largest number of NTRK fusion cases, and the most common fusion pair is ETV6-NTRK3. Adverse drug events (ADEs) obtained from the FAERS database for larotrectinib and entrectinib are 524 and 563, respectively. At the System Organ Class (SOC) level, both drugs have positive signal value for “nervous system disorder”. Other positive signals for entrectinib include “cardiac disorders”, “metabolism and nutrition disorders”, while for larotrectinib, it is “hepatobiliary disorders”. The unexpected signals are also listed in detail. ADEs of the two NTRK inhibitors mainly occur in the first month. The median onset time of ADEs for entrectinib and larotrectinib was 16 days (interquartile range [IQR] 6–86.5) and 44 days ([IQR] 7–136), respectively.Conclusion: Our analysis provides a broad molecular view of the NTRK family. The real-world adverse drug event analysis of entrectinib and larotrectinib contributes to more refined medication management. |
| first_indexed | 2024-03-08T09:30:27Z |
| format | Article |
| id | doaj.art-f3a6c4fba82a49028ed33818ada829d9 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-08T09:30:27Z |
| publishDate | 2024-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-f3a6c4fba82a49028ed33818ada829d92024-01-31T04:40:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122024-01-011510.3389/fphar.2024.13294091329409From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysisZhiwei Cui0Zhen Zhai1De Xie2Lihui Wang3Feiyan Cheng4Siyu Lou5Fan Zou6Rumeng Pan7Shixue Chang8Haoyan Yao9Jing She10Yidan Zhang11Xinyuan Yang12Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, ChinaDepartment of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaCenter for Translational Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, ChinaIntroduction: The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has facilitated the development of precision oncology. Two first-generation NTRK inhibitors (larotrectinib and entrectinib) are currently approved for the treatment of patients with solid tumors harboring NTRK gene fusions. Nevertheless, comprehensive NTRK profiling at the pan-cancer genomic level and real-world studies pertaining to the adverse events of NTRK inhibitors are lacking.Methods: We characterize the genome of NTRK at the pan-cancer level through multi-omics databases such as The Cancer Genome Atlas (TCGA). Through the FDA Adverse Event Reporting System (FAERS) database, we collect reports of entrectinib and larotrectinib-induced adverse events and perform a pharmacovigilance analysis using various disproportionality methods.Results:NTRK1/2/3 expression is lower in most tumor tissues, while they have higher methylation levels. NTRK gene expression has prognostic value in some cancer types, such as breast invasive carcinoma (BRCA). The cancer type with highest NTRK alteration frequency is skin cutaneous melanoma (SKCM) (31.98%). Thyroid carcinoma (THCA) has the largest number of NTRK fusion cases, and the most common fusion pair is ETV6-NTRK3. Adverse drug events (ADEs) obtained from the FAERS database for larotrectinib and entrectinib are 524 and 563, respectively. At the System Organ Class (SOC) level, both drugs have positive signal value for “nervous system disorder”. Other positive signals for entrectinib include “cardiac disorders”, “metabolism and nutrition disorders”, while for larotrectinib, it is “hepatobiliary disorders”. The unexpected signals are also listed in detail. ADEs of the two NTRK inhibitors mainly occur in the first month. The median onset time of ADEs for entrectinib and larotrectinib was 16 days (interquartile range [IQR] 6–86.5) and 44 days ([IQR] 7–136), respectively.Conclusion: Our analysis provides a broad molecular view of the NTRK family. The real-world adverse drug event analysis of entrectinib and larotrectinib contributes to more refined medication management.https://www.frontiersin.org/articles/10.3389/fphar.2024.1329409/fullNTRKgene fusionentrectiniblarotrectinibFAERSadverse drug event |
| spellingShingle | Zhiwei Cui Zhen Zhai De Xie Lihui Wang Feiyan Cheng Siyu Lou Fan Zou Rumeng Pan Shixue Chang Haoyan Yao Jing She Yidan Zhang Xinyuan Yang From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis Frontiers in Pharmacology NTRK gene fusion entrectinib larotrectinib FAERS adverse drug event |
| title | From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis |
| title_full | From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis |
| title_fullStr | From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis |
| title_full_unstemmed | From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis |
| title_short | From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis |
| title_sort | from genomic spectrum of ntrk genes to adverse effects of its inhibitors a comprehensive genome based and real world pharmacovigilance analysis |
| topic | NTRK gene fusion entrectinib larotrectinib FAERS adverse drug event |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2024.1329409/full |
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