Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2

Tanizaki, Junko; Ercan, Dalia; Capelletti, Marzia; Dodge, Michael; Xu, Chunxiao; Bahcall, Magda; Tricker, Erin M.; Butaney, Mohit; Calles, Antonio; Sholl, Lynette M.; Hammerman, Peter S.; Oxnard, Geoffrey R.; Wong, Kwok-Kin

doi:10.1158/0008-5472.can-14-3771

Cited by 32 publications

(28 citation statements)

References 34 publications

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“…Indeed, this initiative has enabled a large number of other more focused studies of common and uncommon tumor types and, in particular, has permitted prospective identification of relatively uncommon genomic variants to facilitate clinical trial enrollment and biomarker studies (46)(47)(48)(49)(50)(51)(52)(53)(54). Migrating to a clinical test, identifying when in the course of a patient's disease genomic profiling should be used, and triaging patients in real-time for clinical trial enrollment should contribute to determining clinical utility on a broader scale.…”

Section: Discussionmentioning

confidence: 99%

Institutional implementation of clinical tumor profiling on an unselected cancer population

Sholl¹,

Khanh²,

Shivdasani³

et al. 2016

JCI Insight

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363

314

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BACKGROUND.Comprehensive genomic profiling of a patient's cancer can be used to diagnose, monitor, and recommend treatment. Clinical implementation of tumor profiling in an enterprisewide, unselected cancer patient population has yet to be reported. METHODS.We deployed a hybrid-capture and massively parallel sequencing assay (OncoPanel) for all adult and pediatric patients at our combined cancer centers. Results were categorized by pathologists based on actionability. We report the results for the first 3,727 patients tested.RESULTS. Our cohort consists of cancer patients unrestricted by disease site or stage. Across all consented patients, half had sufficient and available (>20% tumor) material for profiling; once specimens were received in the laboratory for pathology review, 73% were scored as adequate for genomic testing. When sufficient DNA was obtained, OncoPanel yielded a result in 96% of cases. 73% of patients harbored an actionable or informative alteration; only 19% of these represented a current standard of care for therapeutic stratification. The findings recapitulate those of previous studies of common cancers but also identify alterations, including in AXL and EGFR, associated with response to targeted therapies. In rare cancers, potentially actionable alterations suggest the utility of a "cancer-agnostic" approach in genomic profiling. Retrospective analyses uncovered contextual genomic features that may inform therapeutic response and examples where diagnoses revised by genomic profiling markedly changed clinical management. CONCLUSIONS.Broad sequencing-based testing deployed across an unselected cancer cohort is feasible. Genomic results may alter management in diverse scenarios; however, additional barriers must be overcome to enable precision cancer medicine on a large scale.

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Section: Discussionmentioning

confidence: 99%

Institutional implementation of clinical tumor profiling on an unselected cancer population

Sholl¹,

Khanh²,

Shivdasani³

et al. 2016

JCI Insight

Self Cite

363

314

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“…The oncogenic activation of these FGFR2 fusion proteins relies on the activation of the TK included in the rearrangement and involves enforced dimerization, subsequent transautophosphorylation, and activation of downstream signaling pathways (57,72,73). Transforming and oncogenic potential of FGFR2 fusions (FGFR2-BICC1, FGFR2-PPHLN1, FGFR2-AHCYL1, FGFR2-TACC3) has been proven in vitro (57,72,73,76) and in vivo (72). Furthermore, the presence of FGFR2 fusions seems to predict higher sensitivity to selective FGFR2 inhibitors (57,72,73,76).…”

Section: Tyrosine Kinase Fusion Genesmentioning

confidence: 99%

“…Transforming and oncogenic potential of FGFR2 fusions (FGFR2-BICC1, FGFR2-PPHLN1, FGFR2-AHCYL1, FGFR2-TACC3) has been proven in vitro (57,72,73,76) and in vivo (72). Furthermore, the presence of FGFR2 fusions seems to predict higher sensitivity to selective FGFR2 inhibitors (57,72,73,76). However, the relative oncogenic potential of the different FGFR2 fusions or their sensitivity to specific FGFR2 inhibitors remains unknown and should be extensively investigated in future studies.…”

Section: Tyrosine Kinase Fusion Genesmentioning

confidence: 99%

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

Moeini

Sia

Bardeesy

et al. 2016

Clinical Cancer Research

205

176

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Intrahepatic cholangiocarcinoma (iCCA) is a molecularly heterogeneous hepatobiliary neoplasm with poor prognosis and limited therapeutic options. The incidence of this neoplasm is growing globally. One third of iCCA tumors are amenable to surgical resection, but most cases are diagnosed at advanced stages with chemotherapy as the only established standard of practice. No molecular therapies are currently available for the treatment of this neoplasm. The poor understanding of the biology of iCCA and the lack of known oncogenic addiction loops has hindered the development of effective targeted therapies. Studies with sophisticated animal models defined IDH mutation as the first gatekeeper in the carcinogenic process and led to the discovery of striking alternative cellular origins. RNA-and exome-sequencing technologies revealed the presence of recurrent novel fusion events (FGFR2 and ROS1 fusions) and somatic mutations in metabolic (IDH1/2) and chromatinremodeling genes (ARID1A, BAP1). These latest advancements along with known mutations in KRAS/BRAF/EGFR and 11q13 high-level amplification have contributed to a better understanding of the landscape of molecular alterations in iCCA. More than 100 clinical trials testing molecular therapies alone or in combination with chemotherapy including iCCA patients have not reported conclusive clinical benefits. Recent discoveries have shown that up to 70% of iCCA patients harbor potential actionable alterations that are amenable to therapeutic targeting in early clinical trials. Thus, the first biomarkerdriven trials are currently underway.

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“…The resulting fusion protein undergoes ligand-independent dimerization and subsequent autophosphorylation, which leads to constitutive activation of downstream signaling pathways, such as MAPK (76) (Figure 2). The oncogenic potential of FGFR2 fusions has been demonstrated in vitro (23,28,77,78) and in vivo (28). Screening for fusions by massive parallel sequencing or FISH-based assays has revealed a wide range of IHCC (6-50%) containing FGFR2 fusions, whereas EHCC and GBC rarely do ( Table 1).…”

Section: Fgfr2 Fusionsmentioning

confidence: 99%

“…Screening for fusions by massive parallel sequencing or FISH-based assays has revealed a wide range of IHCC (6-50%) containing FGFR2 fusions, whereas EHCC and GBC rarely do ( Table 1). In preclinical studies, the presence of FGFR2 fusions seems to predict high sensitivity to FGFR2 inhibitors (23,28,73,77,78). This provided the catalyst to target the FGFR pathway specifically in tumors harboring these fusions.…”

Section: Fgfr2 Fusionsmentioning

confidence: 99%

Current biologics for treatment of biliary tract cancers

Zhao

Lim

2017

J. Gastrointest. Oncol.

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Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option. Due to the paucity of effective treatments, BTCs have a dismal prognosis. There is a tremendous need to better understand the disease biology, discover new therapies, and improve clinical outcomes for this challenging disease. Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs. The three BTC histologic subtypes are, in fact, quite molecularly distinct.IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations, whereas EHCC and GBC tend to carry mutations in EGFR, HER2, and MAPK pathway. In light of this emerging knowledge, clinical trials have become more biomarker-driven, which allows capturing of subsets of patients that are most likely to respond to certain therapies. Many new and promising targeted therapeutics are currently in the pipeline.Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials.

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Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2

Cited by 32 publications

References 34 publications

Institutional implementation of clinical tumor profiling on an unselected cancer population

Institutional implementation of clinical tumor profiling on an unselected cancer population

Molecular Pathogenesis and Targeted Therapies for Intrahepatic Cholangiocarcinoma

Current biologics for treatment of biliary tract cancers

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