A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma.

IF 56.7 1区 医学 Q1 ONCOLOGY Annals of Oncology Pub Date : 2024-12-18 DOI:10.1016/j.annonc.2024.12.011
L Goyal, D DiToro, F Facchinetti, E E Martin, P Peng, I Baiev, R Iyer, J Maurer, S Reyes, K Zhang, U Majeed, J E Berchuck, C T Chen, C Walmsley, C Pinto, D Vasseur, J D Gordan, K Mody, M Borad, T Karasic, N Damjanov, B P Danysh, E Wehrenberg-Klee, A R Kambadakone, S K Saha, I D Hoffman, K J Nelson, S Iyer, X Qiang, C Sun, H Wang, L Li, M Javle, B Lin, W Harris, A X Zhu, J M Cleary, K T Flaherty, T Harris, R T Shroff, I Leshchiner, L Parida, R K Kelley, J Fan, J R Stone, N V Uboha, H Hirai, H Sootome, F Wu, D C Bensen, A Hollebecque, L Friboulet, J K Lennerz, G Getz, D Juric
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引用次数: 0

Abstract

Background: Fibroblast growth factor receptor (FGFR) inhibitors have significantly improved outcomes for patients with FGFR-altered cholangiocarcinoma, leading to their regulatory approval in multiple countries. However, as with many targeted therapies, acquired resistance limits their efficacy. A comprehensive, multimodal approach is crucial to characterizing resistance patterns to FGFR inhibitors.

Patients and methods: This study integrated data from six investigative strategies: cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacology. We characterized the diversity, clonality, frequency, and mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR-altered cholangiocarcinoma. Clinical samples were analyzed longitudinally as part of routine care across 10 institutions.

Results: Among 138 patients evaluated, 77 met eligibility, yielding a total of 486 clinical samples. Patients with clinical benefit exhibited a significantly higher rate of FGFR2 kinase domain mutations compared to those without clinical benefit (65% vs 10%, p<0.0001). We identified 26 distinct FGFR2 kinase domain mutations, with 63% of patients harboring multiple. While IC50 assessments indicated strong potency of pan-FGFR inhibitors against common resistance mutations, pharmacokinetic studies revealed that low clinically achievable drug concentrations may underly polyclonal resistance. Molecular brake and gatekeeper mutations predominated, with 94% of patients with FGFR2 mutations exhibiting one or both, whereas mutations at the cysteine residue targeted by covalent inhibitors were rare. Statistical genomics and functional studies demonstrated that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.

Conclusion: Our multimodal analysis led to a model characterizing the biology of acquired resistance, informing the rational design of next-generation FGFR inhibitors. FGFR inhibitors should be small, high-affinity, and selective for specific FGFR family members. Tinengotinib, a novel small molecule inhibitor with these characteristics, exhibited preclinical and clinical activity against key resistance mutations. This integrated approach offers a blueprint for advancing drug resistance research across cancer types.

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来源期刊
Annals of Oncology
Annals of Oncology 医学-肿瘤学
CiteScore
63.90
自引率
1.00%
发文量
3712
审稿时长
2-3 weeks
期刊介绍: Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine. The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings. Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.
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