Detection of heterogeneous resistance mechanisms to tyrosine kinase inhibitors from cell-free DNA

作者：Heather A. Parsons, Conor Messer, Katheryn Santos, Jakob Weiss, David J. Merrell, Brian P. Danysh, Melissa E. Hughes, Gregory J. Kirkner, Ashka Patel, Julian M. Hess, Kerry Sendrick, Chip Stewart, Elizabeth Grant, Kristy Schlueter-Kuck, Albert Grinshpun, Nikhil Wagle, Jamunarani Veeraraghavan, José Pablo Leone, Rachel A. Freedman, Otto Metzger, Rachel Schiff, Eric P. Winer, Sara M. Tolaney, Mothaffar F. Rimawi, Ian E. Krop, Gad Getz, Nancy U. Lin · 发表于：Cell Genomics · 年份：2025 · DOI：10.1016/j.xgen.2025.100987 · 被引用次数：1 · 研究领域：Cancer Genomics and Diagnostics、Lung Cancer Treatments and Mutations、HER2/EGFR in Cancer Research

Though there has been substantial progress in the development of anti-human epidermal growth factor receptor 2 (HER2) therapies to treat HER2-positive metastatic breast cancer (MBC) within the past two decades, most patients still experience disease progression and cancer-related death. HER2-directed tyrosine kinase inhibitors can be highly effective therapies for patients with HER2-positive MBC; however, an understanding of resistance mechanisms is needed to better inform treatment approaches. We performed whole-exome sequencing on 111 patients with 73 tumor biopsies and 120 cell-free DNA samples to assess mechanisms of resistance. In 11 of 26 patients with acquired resistance, we identified alterations in previously characterized genes, such as PIK3CA and ERBB2, that could explain treatment resistance. Mutations in growing subclones identified potential mechanisms of resistance in 5 of 26 patients and included alterations in ESR1, FGFR2, and FGFR4. Additional studies are needed to assess the functional role and clinical utility of these alterations in driving resistance.