The Co-mutational Spectrum Determines the Therapeutic Response in Murine FGFR2 Fusion-Driven Cholangiocarcinoma.
Adenosylhomocysteinase
/ genetics
Animals
Antigens, Neoplasm
/ genetics
Antimetabolites, Antineoplastic
/ pharmacology
Bile Duct Neoplasms
/ genetics
Bile Ducts, Intrahepatic
Cell Proliferation
/ drug effects
Cell Transformation, Neoplastic
/ drug effects
Cholangiocarcinoma
/ genetics
Co-Repressor Proteins
/ genetics
Cyclic AMP Response Element-Binding Protein A
/ genetics
Deoxycytidine
/ analogs & derivatives
Fetal Proteins
/ genetics
Gene Fusion
/ genetics
Liver Neoplasms, Experimental
/ genetics
Mice
Microtubule-Associated Proteins
/ genetics
Mutation
Phenylurea Compounds
/ pharmacology
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins p21(ras)
/ genetics
Pyrimidines
/ pharmacology
Receptor, Fibroblast Growth Factor, Type 2
/ antagonists & inhibitors
Vesicular Transport Proteins
/ genetics
Gemcitabine
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
02
02
2021
received:
06
07
2020
accepted:
11
02
2021
pubmed:
13
3
2021
medline:
14
1
2022
entrez:
12
3
2021
Statut:
ppublish
Résumé
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. 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. 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.
Sections du résumé
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.
Substances chimiques
Antigens, Neoplasm
0
Antimetabolites, Antineoplastic
0
Co-Repressor Proteins
0
Cyclic AMP Response Element-Binding Protein A
0
Fetal Proteins
0
Kctd1 protein, mouse
0
Microtubule-Associated Proteins
0
Phenylurea Compounds
0
Protein Kinase Inhibitors
0
Pyrimidines
0
TACC3 protein, mouse
0
TXLNA protein, mouse
0
Vesicular Transport Proteins
0
periphilin protein, mouse
0
Deoxycytidine
0W860991D6
infigratinib
A4055ME1VK
Receptor, Fibroblast Growth Factor, Type 2
EC 2.7.10.1
Adenosylhomocysteinase
EC 3.3.1.1
IRBIT protein, mouse
EC 3.3.1.1
Hras protein, mouse
EC 3.6.5.2
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Gemcitabine
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1357-1370Informations de copyright
© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
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