Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Saha, Supriya K.; Gordan, John D.; Kleinstiver, Benjamin P.; Vu, Phuong; Najem, Mortada S.; Yeo, J.S.; Shi, Lei; Kato, Yasutaka; Levin, Rebecca S.; Webber, James T.; Damon, Leah J.; Egan, Regina K.; Greninger, Patricia; McDermott, Ultan; Garnett, Mathew J.; Jenkins, Roger L.; Rieger-Christ, Kimberly; Sullivan, Travis; Hezel, Aram F.; Liss, Andrew S.; Mizukami, Yusuke; Goyal, Lipika; Ferrone, Cristina R.; Zhu, Andrew X.; Joung, J. Keith; Shokat, Kevan M.; Benes, Cyril H.; Bardeesy, Nabeel

doi:10.1158/2159-8290.cd-15-1442

Cited by 131 publications

(126 citation statements)

References 46 publications

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“…Of note, IDH -mutant iCCA cells are dependent on SRC activity for survival; the SRC kinase inhibitor dasatinib induced tumour regression of mouse IDH -mutant tumour xenografts 129 . This preclinical work provided the basis for a phase II trial of dasatinib in patients with advanced-stage IDH -mutant iCCA (NCT02428855; Supplementary information S1 (table)).…”

Section: Emerging Molecularly-directed Therapiesmentioning

confidence: 99%

Cholangiocarcinoma — evolving concepts and therapeutic strategies

et al. 2017

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Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.

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Section: Emerging Molecularly-directed Therapiesmentioning

confidence: 99%

Cholangiocarcinoma — evolving concepts and therapeutic strategies

et al. 2017

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“…A phase I/II trial with AG-221 (IDH2 inhibitor) has just completed. A recent study showed that a subset of IHCC tumors with IDH mutations are exquisitely sensitive to the multikinase inhibitor dasatinib (88). This evidence paved the way for designing a phase II trial using dasatinib in IHCC cases harboring mutations in IDH1 or 2 ( Table 2).…”

Section: Idh1/2mentioning

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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“…Investigating how TCA cycle enzyme deregulation affects tumor growth will be crucial to design effective antitumor strategies, including IDH inhibitors or tyrosine kinase inhibitors (TKIs) (87, 90). …”

Section: Metabolic Pathways That Sustain Cancer Cell Survival and Promentioning

confidence: 99%

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

et al. 2016

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Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacological approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this Review, we illustrate how dietary and pharmacological therapies differ in their effect on tumor growth, proliferation and metabolism, and discuss the available preclinical and clinical evidence in favor or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics.

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Isocitrate Dehydrogenase Mutations Confer Dasatinib Hypersensitivity and SRC Dependence in Intrahepatic Cholangiocarcinoma

Cited by 131 publications

References 46 publications

Cholangiocarcinoma — evolving concepts and therapeutic strategies

Cholangiocarcinoma — evolving concepts and therapeutic strategies

Current biologics for treatment of biliary tract cancers

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

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