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

Abstract

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.

Early Change in the Plasma Levels of Circulating Soluble Immune Checkpoint Proteins in Patients with Unresectable Hepatocellular Carcinoma Treated by Lenvatinib or Transcatheter Arterial Chemoembolization

“…play a significant role in the prognosis of HCC [41,42]. For example, the B-type Raf kinase (BRAF) mutation, one of the prognostic factors, could play a role in the response to tyrosine kinase inhibitors [43]. However, we found no significant difference in changes in soluble immune checkpoint protein levels between groups classified according to the response to sorafenib [21] or lenvatinib treatment, possibly due to the small sample size.…”

<p>Overexpression of Rab40b Promotes Hepatocellular Carcinoma Cell Proliferation and Metastasis via PI3K/AKT Signaling Pathway</p>

“…35 Since Rab40b and PI3K orchestrate relevant downstream signalling in HCC biology, it is tempting to speculate a potential combination of Rab40b and PI3K with BRAF-directed therapy. 36 Our results may provide new potential therapeutic targets for the treatment of advanced HCC.…”

MicroRNAs Modulate Drug Resistance-Related Mechanisms in Hepatocellular Carcinoma

“…BRAF protein and KRAS are both upstream regulators in the RAS–RAF–MEK–ERK signaling pathway. In patients with advanced HCC, those with BRAF mutation are more aggressive and resistant to TKI ( 126 ). Another miRNA, miR-550a-3-5p, has also reported to reverse the resistance of HCC cells to BRAF inhibitors through direct targeting of YAP ( 127 ).…”