Clinicogenomic Analysis of <i>FGFR2</i>-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib

Silverman, Ian M.; Hollebecque, Antoine; Friboulet, Luc; Owens, Sherry; Newton, Robert; Zhen, Huiling; Féliz, Luis; Zecchetto, Camilla; Melisi, Davide; Burn, Timothy C.

doi:10.1158/2159-8290.cd-20-0766

Cited by 201 publications

(232 citation statements)

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“…For terminology describing FGFR2 rearrangements, we followed the convention used by Silverman and colleagues (18), whereby FGFR2 rearrangements are referred to as a "fusion" if the breakpoint is within the intron 17 or exon 18 hotspot and the gene partner is previously described or the novel gene is predicted to be an in-frame partner.…”

Section: Patient Datamentioning

confidence: 99%

“…Median BMI (range) 26 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] 27 27 27 29 [26][27][28][29][30][31][32][33][34][35] 27…”

Section: Bmi At Diagnosisunclassified

“…In addition to pemigatinib, other FGFR kinase inhibitors, including Debio 1347, erdafitinib, infigratinib (BGJ398), derazantinib (ARQ 087), and a covalent inhibitor, futibatinib (TAS-120), have demonstrated clinical activity in early trials, with median progression-free survival of approximately 6 months in patients with FGFR2 fusions (3,5,(14)(15)(16)(17). IHCCs with FGFR2 point mutations or amplifications appear to be less sensitive to FGFR inhibitors, highlighting the importance of additional genotype-phenotype analysis of FGFR2 variants (18).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FGFR2Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma

Cleary

Raghavan

et al. 2021

Cancer Discovery

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We conducted next generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EIDs) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR-1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predict sensitivity to FGFR inhibitors in the clinic.Research.

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Section: Patient Datamentioning

confidence: 99%

“…Median BMI (range) 26 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] 27 27 27 29 [26][27][28][29][30][31][32][33][34][35] 27…”

Section: Bmi At Diagnosisunclassified

Section: Introductionmentioning

confidence: 99%

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FGFR2Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma

Cleary

Raghavan

et al. 2021

Cancer Discovery

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“…The reported high frequency of KRAS mutations in patients with FGFR2-fusion positive ICC (8) could not be recapitulated in more recent sequencing studies. Indeed, in a clinical trial, only 2 in 140 patients with FGFR2-rearranged ICC harbored a concomitant KRAS mutation (26).…”

Section: Accepted Articlementioning

confidence: 99%

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

et al. 2021

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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.

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“…Owing to its important role in tumorigenesis, FGFR2 has recently been considered a critical therapeutic target for cancer (18)(19)(20)(21)(22). FGFR inhibitors are classified into several classes, such as pan-FGFR-targeted tyrosine kinase inhibitors (TKIs), multitarget TKIs, and FGFR2 monoclonal antibodies (23).…”

Section: Introductionmentioning

confidence: 99%

A Pancancer Analysis of the Expression Landscape and Clinical Relevance of Fibroblast Growth Factor Receptor 2 in Human Cancers

Huang

et al. 2021

Front. Oncol.

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Background: Fibroblast growth factor receptor 2 (FGFR2) is frequently altered in tumors and one of the top therapeutic targets in cholangiocarcinoma (CHOL) with FGFR2 fusions. Although there have been several studies on individual tumors, a comprehensive analysis of FGFR2 genetic aberrations and their simultaneous clinical implications across different tumors have not been reported.Methods: In this study, we used the large comprehensive datasets available, covering over 10,000 tumor samples across more than 30 cancer types, to analyze FGFR2 abnormal expression, methylation, alteration (mutations/fusions and amplification/deletion), and their clinical associations.Results: Alteration frequency, mutation location distribution, oncogenic effects, and therapeutic implications varied among different cancers. The overall mutation rate of FGFR2 is low in pancancer. CHOL had the highest mutation frequency, and fusion accounted for the major proportion. All these fusion aberrations in CHOL were targetable, and an FDA-approved drug was approved recently. Uterine corpus endometrial carcinoma (UCEC) had the highest number of FGFR2 mutations, and the most frequently mutated positions were S252W and N549K, where the functional impact was oncogenic, but targeted therapy was less effective. Additionally, DNA methylation was associated with FGFR2 expression in several cancers. Moreover, FGFG2 expression and genetic aberrations showed clinical associations with patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets.Conclusions: This study showed the full FGFR2 alteration spectrum and provided a broad molecular perspective of FGFR2 in a comprehensive manner, suggesting some new directions for clinical targeted therapy of cancers.

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Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib

Cited by 201 publications

References 50 publications

FGFR2Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma

FGFR2Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma

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

A Pancancer Analysis of the Expression Landscape and Clinical Relevance of Fibroblast Growth Factor Receptor 2 in Human Cancers

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