Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets

Background and Aims Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer and a highly lethal malignancy. Chemotherapeutic options are limited, but a considerable subset of patients harbors genetic lesions for which targeted agents exist. Fibroblast growth factor receptor 2 (FGFR2) fusions belong to the most frequent and therapeutically relevant alterations in ICC, and the first FGFR inhibitor was recently approved for the treatment of patients with progressed, fusion‐positive ICC. Response rates of up to 35% indicate that FGFR‐targeted therapies are beneficial in many but not all patients. Thus far, no established biomarkers exist that predict resistance or response to FGFR‐targeted therapies in patients with ICC. Approach and Results In this study, we use an autochthonous murine model of ICC to demonstrate that FGFR2 fusions are potent drivers of malignant transformation. Furthermore, we provide preclinical evidence that the co‐mutational spectrum acts not only as an accelerator of tumor development, but also modifies the response to targeted FGFR inhibitors. Using pharmacologic approaches and RNA‐interference technology, we delineate that Kirsten rat sarcoma oncogene (KRAS)–activated mitogen‐activated protein kinase signaling causes primary resistance to FGFR inhibitors in FGFR2 fusion–positive ICC. The translational relevance is supported by the observation that a subset of human FGFR2 fusion patients exhibits transcriptome profiles reminiscent of KRAS mutant ICC. Moreover, we demonstrate that combination therapy has the potential to overcome primary resistance and to sensitize tumors to FGFR inhibition. Conclusions Our work highlights the importance of the co‐mutational spectrum as a significant modifier of response in tumors that harbor potent oncogenic drivers. A better understanding of the genetic underpinnings of resistance will be pivotal to improve biomarker‐guided patient selection and to design clinically relevant combination strategies.

show abstract

“…A). This is in line with the previously described frequent MAPK signaling activation in biliary tract cancers ( 21 ) (Supporting Fig. B).…”

Section: Resultssupporting

confidence: 92%

The Co‐mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion‐Driven Cholangiocarcinoma

et al. 2021

View full text Add to dashboard Cite

show abstract

“…However, due to the rarity of BTC, large-scale clinical trials are challenging to establish. Recently, it was demonstrated that BTC cell lines and organoids have genomic alterations similar to those in primary tumors, indicating that they could be useful in developing and validating therapeutic targets for BTC [ 42 ]. As shown in this study, identifying actionable genes and candidate drugs using KBs could facilitate comprehensive validation using cell lines and organoids.…”

Section: Discussionmentioning

confidence: 99%

Actionability evaluation of biliary tract cancer by genome transcriptome analysis and Asian cancer knowledgebase

et al. 2021

View full text Add to dashboard Cite

Introduction: Treatment options for biliary tract cancer (BTC) are very limited. It is necessary to investigate actionable genes and candidate drugs using a sophisticated knowledgebase (KB) and characterize BTCs immunologically for evaluating the actionability of molecular and immune therapies. Materials and Methods: The genomic and transcriptome data of 219 patients with BTC who underwent surgery were analyzed. Actionable mutations and candidate drugs were annotated using the largest available KB of the Asian population (CancerSCAN ® ). Predictive biomarkers of immune checkpoint inhibitors were analyzed using DNA and RNA sequencing data.Results: Twenty-two actionable genes and 43 candidate drugs were annotated in 74 patients (33.8%). The most frequent actionable genes were PTEN (7.3%), CDKN2A (6.8%), KRAS (6.4%). BRCA2, CDKN2A, and FGFR2 mutations were most frequently identified in case of intrahepatic cholangiocarcinoma. PTEN and CDKN2A mutations were associated with significantly shorter overall survival. PD-L1 and PD-1 expression was significantly higher in case of extrahepatic cholangiocarcinoma and T-cell-high expression. In total, 49.7% of cases were evaluated as having actionability for molecular therapy or immune checkpoint inhibitors.Conclusions: Identifying actionable genes and candidate drugs using the KB contribute to the development of therapeutic drugs and personalized treatment for BTC.

show abstract

“…The work of Akita et al [26] found that IDH1 mutation is typical in iCCA derived from small bile duct as well as the loss of BAP1; in contrast, loss of SMAD4 expression, KRAS mutations, and MDM2 amplification are mainly found in large bile duct iCCA. A very recent study has focused on the in-depth characterization of 22 CCA cell lines, including gallbladder carcinoma, by exome sequencing, copy number, and RNA-seq analyses [27]. This large panel of cell lines, which differ in their site of origin, molecular alterations, and mutational status, represents a valid tool for drug screening tests, in particular for targeted therapy (Table 1).…”

Section: D Models: Cell Lines and Primary Cell Culturesmentioning

confidence: 99%

Evolution of the Experimental Models of Cholangiocarcinoma

Massa

Varamo

Vita

et al. 2020

Cancers

View full text Add to dashboard Cite

Cholangiocarcinoma (CCA) is a rare, aggressive disease with poor overall survival. In advanced cases, surgery is often not possible or fails; in addition, there is a lack of effective and specific therapies. Multidisciplinary approaches and advanced technologies have improved the knowledge of CCA molecular pathogenesis, highlighting its extreme heterogeneity and high frequency of genetic and molecular aberrations. Effective preclinical models, therefore, should be based on a comparable level of complexity. In the past years, there has been a consistent increase in the number of available CCA models. The exploitation of even more complex CCA models is rising. Examples are the use of CRISPR/Cas9 or stabilized organoids for in vitro studies, as well as patient-derived xenografts or transgenic mouse models for in vivo applications. Here, we examine the available preclinical CCA models exploited to investigate: (i) carcinogenesis processes from initiation to progression; and (ii) tools for personalized therapy and innovative therapeutic approaches, including chemotherapy and immune/targeted therapies. For each model, we describe the potential applications, highlighting both its advantages and limits.

show abstract

Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets

Cited by 17 publications

References 48 publications

The Co‐mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion‐Driven Cholangiocarcinoma

The Co‐mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion‐Driven Cholangiocarcinoma

Actionability evaluation of biliary tract cancer by genome transcriptome analysis and Asian cancer knowledgebase

Evolution of the Experimental Models of Cholangiocarcinoma

Contact Info

Product

Resources

About