Quantifying Treatment Resistance in Mixtures of Gastrointestinal Stromal Tumor Cells with BARMIX

Abstract

Targeted therapies in gastrointestinal stromal tumors (GIST) often fail due to heterogeneous resistance mutations arising across metastatic sites. Efficient, rational design of mutation-specific therapies requires the ability to quantify treatment resistance across many genotypes in parallel. Here, we present BARcode MIXture analysis (BARMIX), a platform combining multiplexed experiments with DNA-barcoded cancer cell mixtures in vitro and in vivo, and a probabilistic framework for quantitative assessment of genotype-specific treatment resistance. BARMIX efficiently and accurately recapitulated known clinical resistance patterns in GIST and matched resistance measurements from individual cell lines in vitro and in vivo. This experimental-computational approach provides a scalable and broadly applicable strategy for quantifying treatment responses in complex cell populations, enabling systematic preclinical testing of new drugs and combinations to identify mutation-specific therapeutic options for precision oncology in GIST and beyond.