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RTK25: A Comprehensive Molecular Profiling Strategy in Cholangiocarcinoma Using an Integrated Bioinformatics Approach.

ABSTRACT: Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies that primarily originate from the bile duct. Tumor heterogeneity is a prime characteristic of CCA and considering the scarcity of approved targeted therapy drugs, this makes precision oncology impractical in CCA. Stratifying patients based on their molecular signature and biomarker-guided therapy may offer a conducive solution. Receptors tyrosine kinases (RTK) are potential targets for novel therapeutic strategies in CCA as RTK signaling is dysregulated in CCA. This study aims to identify targetable RTK profile in CCA using a bioinformatic approach. We discovered that CCA samples could be grouped into molecular subtypes based on the gene expression profile of selected RTKs (RTK25). Using the RTK25 gene list, we discovered five distinct molecular subtypes of CCA in this cohort. Tyrosine kinase inhibitors that target each RTK profile and their subsequent molecular signatures were also discovered. These results suggest that certain RTKs correlate with each other, indicating that tailored dual inhibition of RTKs may be more favorable than monotherapy. The results from this study can direct future investigative attention towards validating this concept in in vivo and in vitro systems. Ultimately, this will facilitate biomarker-guided clinical trials for the successful approval of novel therapeutic options in CCA.

SUBMITTER: Balasubramanian B

PROVIDER: S-EPMC8469883 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCholangiocarcinoma (CCA) is a devastating malignancy and has a very poor prognosis if tumors spread outside the liver. Understanding the molecular mechanisms underlying the CCA progression will likely yield therapeutic approaches toward treating this deadly disease.AimTo determine the molecular pathogenesis in CCA progression.MethodsIn silico analysis, in vitro cell culture, CCA transgenic animals, histological, and molecular assays were adopted to determine the molecular pathogenesis.ResultsThe transcriptomic data of human CCA samples were retrieved from The Cancer Genome Atlas (TGCA, CHOL), European Bioinformatics Institute (EBI, GAD00001001076), and Gene Expression Omnibus (GEO, GSE107943) databases. Using Gene set enrichment analysis, the cell cycle and Notch related pathways were demonstrated to be significantly activated in CCA in TCGA and GEO datasets. We, through differentially expressed genes, found several cell cycle and notch associated genes were significantly up-regulated in cancer tissues when compared with the non-cancerous control samples. The associated genes, via quantitative real-time PCR and western blotting assays, were further examined in normal human cholangiocytes, CCA cell lines, mouse normal bile ducts, and mouse CCA tumors established by specifically depleting P53 and expressing KrasG12D mutation in the liver. Consistently, we validated that the cell cycle and Notch pathways are up-regulated in CCA cell lines and mouse CCA tumors. Interestingly, targeting cell cycle and notch pathways using small molecules also exhibited significant beneficial effects in controlling tumor malignancy. More importantly, we demonstrated that several cell cycle and Notch associated genes are significantly associated with poor overall survival and disease-free survival using the Log-Rank test.ConclusionIn summary, our study comprehensively analyzed the gene expression pattern of CCA samples using publicly available datasets and identified the cell cycle and Notch pathways are potential therapeutic targets in this deadly disease.

Project description:BackgroundCholangiocarcinoma (CCA) is associated with poor outcomes and limited treatment options, leading to increased use of targeted therapies for its management. Here, we performed one of the largest single-centre reviews evaluating outcomes following personalised targeted agents in CCA patients.MethodsAll consecutive CCA patients receiving systemic therapy between January 2010 and April 2023 at UCLH were included. The primary objective of this study was to evaluate treatment response, survival outcomes and predictors of clinical benefit in CCA patients treated with molecularly guided therapies. Patient demographic factors, disease characteristics and survival outcomes were evaluated using the Kaplan-Meier method and Cox proportional-hazards models.ResultsOf the 227 consecutive CCA patients, 162 (71%) had molecular profiling, of whom 56 (35%) were eligible and 55 received molecular-targeted treatment. CCA histological classifications comprised intrahepatic (N = 32), extrahepatic (N = 11), hilar (N = 4) and unknown (N = 9) subtypes. Most patients received targeted agents based on genomic profiling in a second treatment line setting (N = 34). Frequently observed genomic alterations occurred in the FGFR2 (N = 21), IDH1 (N = 7) and BRCA2 (N = 6) genes. Median progression-free survival (PFS) following first-, second- and third-line systemic therapy and overall survival (OS) were 8.44 (95% CI, 7.49-12.78), 5.65 (95% CI, 3.71-7.13), 5.55 (2.79-12.58) and 29.01 (24.21-42.91) months, respectively. CCA subtype and FGFR/BRCA molecular aberration status were not associated with PFS or OS. However, a prior CCA-related surgical history was predictive of OS (p = 0.02). Stratification by best overall response to second-line targeted agents demonstrated an association with PFS (p = 0.002) and OS (p = 0.02). Duration of treatment with second-line targeted therapy was associated with OS (p < 0.001).ConclusionsPatients receiving targeted therapeutics achieved promising outcomes, especially those attaining a favourable treatment response and those receiving targeted agents for longer periods. Liquid biopsies can reliably provide information on extended molecular profiling to aid patient selection for personalised therapies.

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RTK25: A Comprehensive Molecular Profiling Strategy in Cholangiocarcinoma Using an Integrated Bioinformatics Approach.

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