Hanieh Taheri, Yang Li, Kevin M Huang, Eman Ahmed, Yan Jin, Thomas Drabison, Yan Yang, Samuel K Kulp, Nicholas A Young, Junan Li, Xiaolin Cheng, Kara N Corps, Christopher C Coss, Jennifer E Vaughn, Maryam B Lustberg, Alex Sparreboom, Shuiying Hu
{"title":"OATP1B-type transport function is a determinant of aromatase inhibitor-associated arthralgia susceptibility.","authors":"Hanieh Taheri, Yang Li, Kevin M Huang, Eman Ahmed, Yan Jin, Thomas Drabison, Yan Yang, Samuel K Kulp, Nicholas A Young, Junan Li, Xiaolin Cheng, Kara N Corps, Christopher C Coss, Jennifer E Vaughn, Maryam B Lustberg, Alex Sparreboom, Shuiying Hu","doi":"10.1158/2767-9764.CRC-24-0475","DOIUrl":null,"url":null,"abstract":"<p><p>Aromatase inhibitors (AIs) such as anastrozole, letrozole and exemestane are used as adjuvant treatment for postmenopausal women with hormone receptor-positive breast cancer. The interindividual pharmacokinetic variability seen with AIs is extensive, and this phenomenon may have important ramification for AI-associated arthralgia, a common toxicity of which the etiology remains unclear. We speculated that hepatic uptake transporters involved in the elimination of AIs play a crucial role in explaining this pharmacologic variability. Using an array of in silico, in vitro, in vivo, and human studies, we identified OATP1B1 and OATP1B3 (in humans) as well as the murine orthologue Oatp1b2 as transporters that regulate the initial step in the elimination of AIs. Genetic deficiency of this transport mechanism in mice was associated with elevated plasma levels of AIs and with concurrent increases in treatment-related arthralgia. In line with these findings, we found that low hepatic OATP1B-type transporter activity in patients with breast cancer was associated with an increase in AI-associated arthralgia. These findings shed light on the rate-limiting step in the elimination of AIs and suggest a rationale for the potential implementation of transporter biomarkers to predict susceptibility to AI-associated arthralgia and ultimately mitigate this debilitating toxicity.</p>","PeriodicalId":72516,"journal":{"name":"Cancer research communications","volume":" ","pages":""},"PeriodicalIF":2.0000,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer research communications","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1158/2767-9764.CRC-24-0475","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Aromatase inhibitors (AIs) such as anastrozole, letrozole and exemestane are used as adjuvant treatment for postmenopausal women with hormone receptor-positive breast cancer. The interindividual pharmacokinetic variability seen with AIs is extensive, and this phenomenon may have important ramification for AI-associated arthralgia, a common toxicity of which the etiology remains unclear. We speculated that hepatic uptake transporters involved in the elimination of AIs play a crucial role in explaining this pharmacologic variability. Using an array of in silico, in vitro, in vivo, and human studies, we identified OATP1B1 and OATP1B3 (in humans) as well as the murine orthologue Oatp1b2 as transporters that regulate the initial step in the elimination of AIs. Genetic deficiency of this transport mechanism in mice was associated with elevated plasma levels of AIs and with concurrent increases in treatment-related arthralgia. In line with these findings, we found that low hepatic OATP1B-type transporter activity in patients with breast cancer was associated with an increase in AI-associated arthralgia. These findings shed light on the rate-limiting step in the elimination of AIs and suggest a rationale for the potential implementation of transporter biomarkers to predict susceptibility to AI-associated arthralgia and ultimately mitigate this debilitating toxicity.