Signaling networks in cholangiocarcinoma molecular pathogenesis, targeted therapies and drug resistance

Laura Fouassier 1, * Marco Marzioni 2, * Marta B Afonso 3 Steven Dooley 4 Kevin Gaston 5 Gianluigi Giannelli Cecilia M P Rodrigues 3 Elisa Lozano 6 Serena Mancarella Oreste Segatto 7 Javier Vaquero 1 Jose J G Marin 6, * Cedric Coulouarn 8, *
* Corresponding author
1 CR Saint-Antoine - Centre de Recherche Saint-Antoine
2 UNIVPM - Università Politecnica delle Marche [Ancona]
3 ULISBOA - Universidade de Lisboa
4 Heidelberg University
5 UON - University of Nottingham, UK
6 Universidad de Salamanca
7 IRCCS - Istituti di Ricovero e Cura a Carattere Scientifico
8 NuMeCan - Nutrition, Métabolismes et Cancer
Abstract : Cholangiocarcinoma (CCA) is a deadly disease. While surgery may attain cure in a minor fraction of cases, therapeutic options in either the adjuvant or advanced setting are limited. The possibility of advancing the efficacy of therapeutic approaches to CCA relies on understanding its molecular pathogenesis and developing rational therapies aimed at interfering with oncogenic signaling networks that drive and sustain cholangiocarcinogenesis. These efforts are complicated by the intricate biology of CCA, which integrates not only the driving force of tumor-cell-intrinsic alterations at the genetic and epigenetic level, but also pro-tumorigenic cues conveyed to CCA cells by different cell types present in the rich tumor stroma. Herein, we review our current understanding of the mechanistic bases underpinning the activation of major oncogenic pathways causative of CCA pathogenesis. We subsequently discuss how this knowledge is being exploited to implement rationale-based and genotype-matched therapeutic approaches that predictably will radically transform CCA clinical management in the next decade. We conclude by highlighting mechanisms of therapeutic resistance in CCA and reviewing innovative approaches to combat resistance at the pre-clinical and clinical level.
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UNIV-RENNES1 | SORBONNE-UNIVERSITE | UNIV-RENNES | UR1-UFR-SVE | NUMECAN | U938 | SU-MEDECINE

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Laura Fouassier, Marco Marzioni, Marta B Afonso, Steven Dooley, Kevin Gaston, et al.. Signaling networks in cholangiocarcinoma molecular pathogenesis, targeted therapies and drug resistance. Liver International, Wiley-Blackwell, 2019, Cholangiocarcinoma, 39 (S1), pp.43-62. ⟨10.1111/liv.14102⟩. ⟨hal-02087897⟩

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