Polyclonal Secondary <i>FGFR2</i> Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma

Goyal, Lipika; Saha, Supriya K.; Liu, Leah Y.; Siravegna, Giulia; Leshchiner, Ignaty; Ahronian, Leanne G.; Lennerz, Jochen K.; Vu, Phuong; Deshpande, Vikram; Kambadakone, Avinash; Mussolin, Benedetta; Reyes, Stephanie; Henderson, Laura E.; Sun, Jiaoyuan Elisabeth; Seventer, Emily E. Van; Gurski, Joseph M.; Baltschukat, Sabrina; Schacher-Engstler, Barbara; Barys, Louise; Stamm, Christelle; Furet, Pascal; Ryan, David P.; Stone, James R.; Iafrate, A. John; Getz, Gad; Porta, Diana Graus; Tiedt, Ralph; Bardelli, Alberto; Juric, Dejan; Corcoran, Ryan B.; Bardeesy, Nabeel; Zhu, Andrew X.

doi:10.1158/2159-8290.cd-16-1000

Cited by 401 publications

(295 citation statements)

References 45 publications

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“…As seen with other oncogene addicted tumors treated with tyrosine kinase inhibitors, acquired resistance limited the durability of response in some patients. Goyal, et al reported the first evidence of clinically acquired resistance to FGFR inhibition in an analysis of three patients with FGFR2-fusion positive ICC who were treated with BGJ398 (129). Sequencing of cell-free DNA and biopsy samples collected at baseline and post-progression revealed polyclonal secondary mutations in the FGFR2 kinase domain, including the gatekeeper mutation FGFR2 V564F in all three patients.…”

Section: Emerging Therapiesmentioning

confidence: 99%

New Horizons for Precision Medicine in Biliary Tract Cancers

et al. 2017

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Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients presents with resectable disease; however, relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been suggested. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g. radioembolization or external beam radiation); pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next generation sequencing analyses have identified actionable mutations (e.g. FGFR fusion rearrangements and IDH-1 and -2 mutations) with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC is rapidly evolving and the subject of this review.

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Section: Emerging Therapiesmentioning

confidence: 99%

New Horizons for Precision Medicine in Biliary Tract Cancers

et al. 2017

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“…Reversible inhibitors of FGFR such as BGJ398 appear to be subject to resistance development as has been demonstrated in recent studies of resistant patients [26]. Irreversible FGFR inhibition by novel covalently binding small molecules may circumvent this back draw of earlier compounds [27].…”

Section: Genetic Mutations and Therapeutic Opportunitiesmentioning

confidence: 99%

Targeting cholangiocarcinoma

Mertens

Rizvi

Gores

2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA. Clinical trials targeting these specific driver mutations are in progress. However, The Tumor Genome Atlas (TCGA) marker analysis of CCA also highlights the tremendous molecular heterogeneity of this cancer rendering comprehensive employment of targeted therapies challenging. CCA also display a rich tumor microenvironment which may be easier to target. For example, targeting cancer associated fibroblasts for apoptosis with BH3-mimetics and/or and reversing T-cell exhaustion with immune check point inhibitors may help aid in the treatment of this otherwise devastating malignancy. Combinatorial therapy attacking the tumor microenvironment plus targeted therapy may help advance treatment for CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.

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“…Recently, the analysis of autopsy specimens has reemerged as a valuable tool to understand cancer heterogeneity and patterns of evolution. 15,16 The major advantages are: (1) it provides a large quantity of samples, (2) it allows extensive sampling of different tumour nodules and metastatic sites and (3) it provides tissue from advanced/aggressive tumours. Indeed, recent studies using autopsy samples have provided novel insights into cancer progression in pancreatic 16 and prostate 17 cancer.…”

Section: Introductionmentioning

confidence: 99%

A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites

et al. 2019

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Aims Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages, and paired primary–metastatic comparisons between samples from the same patient are difficult. Methods and results We report the evaluation of 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules analysed. The study included morphological assessment, immunohistochemistry and mutation status of the TERT promoter, the most frequently mutated gene in HCC. We confirm a strong predilection of HCC for lung dissemination, including subclinical micrometastases (unrecognised during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; macrovascular invasion; high histological, nuclear and architectural grades; and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significantly higher K19 and EpCAM expression than primary liver tumours. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule. Conclusions This study suggests limited heterogeneity in metastatic sites compared to primary tumour sites.

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Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma

Cited by 401 publications

References 45 publications

New Horizons for Precision Medicine in Biliary Tract Cancers

New Horizons for Precision Medicine in Biliary Tract Cancers

Targeting cholangiocarcinoma

A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites

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