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

Abstract

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.

Targeting FGFR for cancer therapy

“…A noteworthy finding is that 90% of patients diagnosed with ICC and having KRAS mutations also showed positive findings for FGFR 2 fusions, suggesting a potential collaborative role in promoting the progression of malignant tumors [ 65 ]. Consequently, it is hypothesized that the occurrence of FGFR 2 fusion in ICC might serve as an initial genetic occurrence that fosters the initiation and progression of tumorigenesis [ 66 ].…”

Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance

“…A few studies have indicated that the use of genetically defined cellular and animal models can advance the discovery of actionable vulnerabilities associated with druggable iCCA oncogenic drivers. Specifically, three independent studies found that RAS-ERK signalling is necessary and sufficient to support the oncogenic activity of FGFR2 fusions in PDXs 91 , GEMMs 175 and organoid-based iCCA models 167 , and that combination therapies capable of more robust and durable suppression of RAS-ERK improve the therapeutic efficacy of clinically approved FGFR tyrosine kinase inhibitors 91,167,175 . Likewise, IDH1/KRAS-driven models have revealed that pharmacological targeting of mutated IDH1 sensitizes iCCA to host-mediated immune responses, which can be enhanced by concomitant administration of immune checkpoint inhibitors 121 .…”

Molecular Subtypes and Precision Oncology in Intrahepatic Cholangiocarcinoma

“…Gate keeper mutations can prevent the drug from accessing the hydrophobic pocket due to steric hindrance, and off-target resistance can impair longlasting response to FGFR inhibitors by acquiring new (epi-) genomic alterations that lead to activation of alternative signaling pathways [45]. In addition, the co-mutational status of the tumors is another relevant factor that may influence treatment response and has to be considered [46].…”