The Landscape of Genomic Alterations in Receptor Tyrosine Kinase Pathways in Biliary Cancers: Implications for Targeted Therapies

Ioannis A Voutsadakis

doi:10.1007/s12029-025-01335-4

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The Landscape of Genomic Alterations in Receptor Tyrosine Kinase Pathways in Biliary Cancers: Implications for Targeted Therapies

Journal article

Open access

Peer reviewed

The Landscape of Genomic Alterations in Receptor Tyrosine Kinase Pathways in Biliary Cancers: Implications for Targeted Therapies

Ioannis A Voutsadakis

Journal of gastrointestinal cancer, Vol.56(1), 207

10/18/2025

DOI: 10.1007/s12029-025-01335-4

PMCID: PMC12535519

PMID: 41109905

Appears in UI Libraries Support Open Access

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Abstract

Biliary carcinomas are aggressive cancers with a high mortality rate. When metastatic, biliary cancers are associated with a short survival and low response to treatments. The first line therapy of metastatic biliary carcinomas consists of a platinum doublet chemotherapy combination with an immune checkpoint inhibitor and results in a median overall survival in the range of approximately 12-13 months, with 20% to 25% of patients surviving at 2 years. Second line chemotherapy options based on fluoropyrimidines are associated with a median survival of less than 6 months. Genomic studies in recent years have clarified molecular aspects of biliary cancers and have confirmed the molecular heterogeneity between the intrahepatic, extrahepatic and gallbladder primary sites. Publicly available genomic cohorts of biliary cancer primary locations were interrogated for common mutations and copy number alterations with a focus on receptor tyrosine kinases and their signal transduction pathways. Specific mutations and structural alterations have different prevalence depending on the primary location. Alterations in receptor tyrosine kinases and the transduction pathways originating from them show differential prevalence in the primary locations of the biliary cancers and create diverse treatment opportunities that can be harnessed for drug development. Approximately 49% of intrahepatic, 57.6% of gallbladder, and 66% of extrahepatic carcinomas harbor RTK pathway alterations. Targeted therapies for individual components of these kinase receptors and pathways, including FGFR2, HER2, BRAF and others, have already been introduced in clinical practice for the treatment of patients with biliary tumors bearing alterations in these genes. The findings underscore the need for primary site-driven genomic testing to guide therapy selection. The current analysis discusses strategies to create opportunities for clinically available targeted therapies.

Genomics

Mutation

Biliary Tract Neoplasms - drug therapy

Biliary Tract Neoplasms - genetics

Biliary Tract Neoplasms - pathology

Humans

Molecular Targeted Therapy - methods

Receptor Protein-Tyrosine Kinases - antagonists & inhibitors

Receptor Protein-Tyrosine Kinases - genetics

Receptor Protein-Tyrosine Kinases - metabolism

Signal Transduction - drug effects

Signal Transduction - genetics

UIOWA OA Agreement

Details

Title: Subtitle: The Landscape of Genomic Alterations in Receptor Tyrosine Kinase Pathways in Biliary Cancers: Implications for Targeted Therapies
Creators: Ioannis A Voutsadakis - University of Iowa
Resource Type: Journal article
Publication Details: Journal of gastrointestinal cancer, Vol.56(1), 207
DOI: 10.1007/s12029-025-01335-4
PMID: 41109905
PMCID: PMC12535519
NLM abbreviation: J Gastrointest Cancer
ISSN: 1941-6628
eISSN: 1941-6636
Publisher: Springer Nature
Language: English
Date published: 10/18/2025
Academic Unit: Internal Medicine
Record Identifier: 9985015991802771

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