Signalling networks in cholangiocarcinoma: Molecular pathogenesis, targeted therapies and drug resistance
Laura Fouassier1, Marco Marzioni2, Marta B Afonso3
1Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
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 signalling networks that drive and sustain cholangiocarcinogenesis. These efforts are complicated by the intricate biology of CCA, which integrates not only the driving force of tumour 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 tumour 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 the mechanisms of therapeutic resistance in CCA and reviewing innovative approaches to combat resistance at the preclinical and clinical level.
Insights
Cholangiocarcinoma (CCA) is a deadly bile duct cancer. Understanding its molecular drivers and tumor microenvironment is key to developing targeted therapies and overcoming treatment resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Pathogenesis
Background:
- Cholangiocarcinoma (CCA) presents limited therapeutic options beyond surgery.
- CCA pathogenesis involves complex tumor-intrinsic alterations and tumor stroma interactions.
- Effective CCA treatment requires understanding oncogenic signaling pathways.
Purpose of the Study:
- To review the mechanistic basis of oncogenic pathway activation in CCA.
- To discuss the development of rational, genotype-matched therapies for CCA.
- To highlight therapeutic resistance mechanisms and innovative strategies in CCA.
Main Methods:
- Review of current literature on CCA molecular pathogenesis.
- Analysis of oncogenic signaling pathways driving cholangiocarcinogenesis.
- Discussion of preclinical and clinical approaches to combat CCA resistance.
Main Results:
- Major oncogenic pathways driving CCA have been elucidated.
- Rationale-based and genotype-matched therapies are emerging for CCA.
- Mechanisms of therapeutic resistance in CCA are being identified.
Conclusions:
- Advances in understanding CCA molecular biology are paving the way for transformative treatments.
- Targeting oncogenic pathways and overcoming resistance are crucial for improving CCA patient outcomes.
- Future CCA management will likely involve personalized, mechanism-based therapeutic strategies.
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