Targeted kinase inhibitor modulates cross resistance and collateral sensitivity in the gut microbiome

Changes in the human gut microbiome have been linked to various health outcomes, including responses to cancer drugs. Despite the wide use of small molecule cancer therapies, their antimicrobial activity and impact on gut bacteria have not been assessed systematically. In this work, we leveraged large-scale experimentation, genomics, and adaptive evolution to identify human gut bacteria impacted by off-target toxicities of top anticancer compounds. Distinct family-level shifts were seen across gut microbiomes for 13 of 41 first-line cancer therapies tested, including several targeted kinase inhibitors (TKIs). Comparative genomic and transcriptomic studies of gut bacterial isolates revealed conserved bacterial pathways modulated by TKI toxicity, notably those involved in antibiotic resistance. Adaptive evolution of Bacteroides fragilis and Phocaeicola vulgatus isolates exposed to the first-line TKI sorafenib produced lineage-specific cross-resistance and collateral sensitivity profiles across seven common antibiotic classes. In the pathobiont B. fragilis, evolved TKI resistance was caused by mutations in genetic regulators that increased expression of tripartite efflux systems. This work highlights the impact of cancer therapeutic collateral toxicity on the gut microbiome and its potential to reshape the gut resistome.