Cholangiocarcinoma Targeted Therapies: Mechanisms of Action and Resistance

Cholangiocarcinoma is an aggressive bile duct malignancy with heterogeneous genomic features. Although most patients receive standard-of-care chemotherapy/immunotherapy, genomic changes that can be targeted with established or emerging therapeutics are common. Accordingly, precision medicine strategies are transforming the next-line treatment for patient subsets. Hotspot IDH1 mutations and activating fibroblast growth factor receptor 2 fusions occur frequently, and small-molecule inhibitors against these alterations are US Food and Drug Administration approved. Translational and basic science studies have elucidated the mechanisms of response and resistance in cholangiocarcinoma, providing insights into these targets that extend to other cancers. Additional US Food and Drug Administration-approved and National Comprehensive Cancer Network guideline-recommended treatments for recurrent genomic changes include BRAF inhibition (BRAF-V600E) and trastumazab deruxtecan (human epidermal growth factor receptor 2 amplification). Furthermore, ongoing clinical trials show promising results with KRAS inhibition (KRAS-codon 12 mutations), PRTM5 inhibition, alone or with methylthioadenosine inhibition (5-methylthioadenosine phosphorylase deletion), and murine double minute 2 inhibition (murine double minute 2 amplification). Despite these advances, the rate, depth, and duration of response to each treatment need improvement. Moreover, many patients do not have currently targetable genotypes. This review examines the clinical efficacy and mechanisms of resistance associated with these treatments, as well as insights into the molecular and biological effects of pathway activation and inhibition, based on study of patient samples and preclinical models. It also explores strategies to overcome resistance and possible precision medicine approaches for additional patient subsets.