Targeted therapies in biliary tract cancer—when precision becomes imprecise

Advanced biliary tract cancers (BTCs) have gained notoriety among gastrointestinal tumours for their comparatively high incidence of actionable alterations and their compelling benefit from targeted therapies matched to these alterations. Such successes are exemplified by BTC-specific approvals of fibroblast growth factor receptor (FGFR) inhibitors for tumours with <i>FGFR2</i> rearrangements, as well as mutant isocitrate dehydrogenase 1 inhibitors. Nevertheless, there is a clear absence of therapeutic benefit in a subset of patients despite their tumours fulfilling the current molecular criteria for treatment with these drugs. This results in inefficient management of patients with otherwise bleak prognosis, as well as considerable financial burden. Even among responders, the duration of response is limited, a clinical observation that could be considered unusual as these inhibitors typically target driver genes hypothesised to be responsible for tumour formation. However, BTCs exhibit oncogenic addiction to signalling networks rather than individual genes, and by extension, therapeutic response is dependent on these signalling networks rather than simply the status of the specific target gene. Primary resistance is mediated by co-occurring genetic (DNA) and non-genetic (transcriptional, translational, post-translational) alterations in members of signalling networks that are upstream, downstream, or in parallel pathways to the target alteration. Refining the molecular criteria to select patients is a necessary next step, by incorporating co-occurrence of resistance biomarkers as individual parameters or into predictors of treatment benefit. Characterising the molecular bases of resistance to targeted therapies will fuel next-generation combination treatments, maximising the catchment of responders and enhancing the duration of response.