Reference Detail

Ref Type

Journal Article

PMID

(33709535)

Authors

Kendre G, Marhenke S, Lorz G, Becker D, Reineke-Plaaß T, Poth T, Murugesan K, Kühnel F, Woller N, Wirtz RM, Pich A, Marquardt JU, Saborowski M, Vogel A, Saborowski A

Title

The co-mutational spectrum determines the therapeutic response in murine FGFR2 fusion - driven cholangiocarcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Hepatology (Baltimore, Md.)			2021 Mar 11	1357-1370	Hepatology

URL

Abstract Text

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 ICC patients.In this study, we use an autochthonous murine model of ICC to demonstrate that FGFR2 fusions are potent drivers of malignant transformation. Further, we provide preclinical evidence that the co-mutational spectrum not only acts as an accelerator of tumor development, but also modifies the response to targeted FGFR inhibitors. Using pharmacologic approaches and RNAi-technology, we delineate that KRAS-activated MAPK 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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References