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The following is a summary of “A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma” published in the December 2024 issue of Oncology by Goyal et al.    

Fibroblast growth factor receptor (FGFR) inhibitors have improved outcomes for people with FGFR-altered cholangiocarcinoma, but acquired resistance reduces their effectiveness.  

Researchers conducted a retrospective study to understand the mechanisms of acquired resistance to FGFR inhibitors in people with FGFR-altered cholangiocarcinoma.  

They integrated data from 6 investigative strategies (cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacology) to evaluate resistance patterns in 77 eligible people with FGFR-altered cholangiocarcinoma, analyzing 486 clinical samples from 10 institutions.  

The results showed that people who experienced clinical benefit had a significantly higher rate of FGFR2 kinase domain mutations compared to those who did not experience clinical benefit (65% vs. 10%, P<0.0001), 26 distinct FGFR2 kinase domain mutations, with 63% of people having multiple mutations were identified. While pan-FGFR inhibitors showed strong potency against common resistance mutations, pharmacokinetic studies revealed that low, clinically achievable drug concentrations might cause polyclonal resistance. Molecular brake and gatekeeper mutations were common, with 94% of people with FGFR2 mutations exhibiting 1 or both. Mutations targeting the cysteine residue of covalent inhibitors were rare. Statistical genomics and functional studies showed that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.  

They concluded that the multimodal analysis provided a framework for developing next-generation FGFR inhibitors. These inhibitors should be small, high-affinity, and selective, as shown by the preclinical and clinical efficacy of tinengotinib against key resistance mutations.  

Source: annalsofoncology.org/article/S0923-7534(24)04990-1/fulltext