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Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies

1
Medical Oncology Unit, “S. Cuore di Gesù” Hospital, 73014 Gallipoli, Italy
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Department of Surgery and Liver Transplantation, Policlinico di Bari, 70124 Bari, Italy
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Medical Oncology Unit, National Cancer Research Centre, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
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Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, 70124 Bari, Italy
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Medical Thoracic Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Viale Orazio Flacco, 65, 70124 Bari, Italy
6
Scientific direction, National Cancer Research Centre, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy
*
Authors to whom correspondence should be addressed.
Medicina 2019, 55(12), 754; https://doi.org/10.3390/medicina55120754
Received: 15 September 2019 / Revised: 11 November 2019 / Accepted: 15 November 2019 / Published: 21 November 2019
The few therapeutic strategies for advance hepatocellular carcinoma (HCC) on poor knowledge of its biology. For several years, sorafenib, a tyrosine kinase inhibitors (TKI) inhibitor, has been the approved treatment option, to date, for advanced HCC patients. Its activity is the inhibition of the retrovirus-associated DNA sequences protein (RAS)/Rapidly Accelerated Fibrosarcoma protein (RAF)/mitogen-activated and extracellular-signal regulated kinase (MEK)/extracellular-signal regulated kinases (ERK) signaling pathway. However, the efficacy of sorafenib is limited by the development of drug resistance, and the major neuronal isoform of RAF, BRAF and MEK pathways play a critical and central role in HCC escape from TKIs activity. Advanced HCC patients with a BRAF mutation display a multifocal and/or more aggressive behavior with resistance to TKI. Moreover, also long non-coding RNA (lnc-RNA) have been studied in epigenetic studies for BRAF aggressiveness in HCC. So far, lnc-RNA of BRAF could be another mechanism of cancer proliferation and TKI escape in HCC and the inhibition could become a possible strategy treatment for HCC. Moreover, recent preclinical studies and clinical trials evidence that combined treatments, involving alternative pathways, have an important role of therapy for HCC and they could bypass resistance to the following TKIs: MEK, ERKs/ribosomal protein S6 kinase 2 (RSK2), and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR). These initial data must be confirmed in clinical studies, which are currently ongoing. Translational research discoveries could create new strategies of targeted therapy combinations, including BRAF pathway, and they could eventually bring light in new treatment of HCC. View Full-Text
Keywords: BRAF; hepatocellular carcinoma; liver microenvironment; MAPK pathway; MEK; Sorafenib; TKI BRAF; hepatocellular carcinoma; liver microenvironment; MAPK pathway; MEK; Sorafenib; TKI
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Gnoni, A.; Licchetta, A.; Memeo, R.; Argentiero, A.; Solimando, A.G.; Longo, V.; Delcuratolo, S.; Brunetti, O. Role of BRAF in Hepatocellular Carcinoma: A Rationale for Future Targeted Cancer Therapies. Medicina 2019, 55, 754.

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