The multifaceted anti-cancer effects of BRAF-inhibitors

Abstract

The BRAF gene is commonly involved in normal processes of cell growth and differentiation. The BRAF (V600E) mutation is found in several human cancer, causing an increase of cell proliferation due to a modification of the ERK/MAPK-signal cascade. In particular, BRAFV600E mutation is found in those melanoma or thyroid cancer refractory to the common therapy and with a more aggressive phenotype. BRAF V600E was found to influence the composition of the so-called tumour microenvironment modulating both solid (immune-cell infiltration) and soluble (chemokines) mediators, which balance characterize the ultimate behaviour of the tumour, making it more or less aggressive. In particular, the presence of BRAFV600E mutation would be associated with a change of this balance to a more aggressive phenotype of the tumour and a worse prognosis. The investigation of the possible modulation of those components of tumour microenvironment is nowadays object of several studies as a new potential target therapy in those more complicated cases. At present several clinical trials both in melanoma and thyroid cancer are using BRAF-inhibitors with encouraging results, which are derived also from numerous in vitro pre-clinical studies aimed at evaluate the possible modulation of immune-cell density and of specific pro-tumorigenic chemokine secretion (CXCL8 and CCL2) by several BRAF-inhibitors in the context of melanoma and thyroid cancer. This review will encompass in vitro and in vivo studies which investigated the modulation of the tumour microenvironment by BRAF-inhibitors, highlighting also the most recent clinical trials with a specific focus on melanoma and thyroid cancer.

Keywords: BRAF; BRAF-inhibitors; CXCL8; chemokines; tumor microenvironment.

Figure 1

(A) Representation of normal BRAF pathway. The sequence of the cascade RAF-BRAF-MEK-ERK starting from the activation of Thyrosin kinase receptor, regulates normal cell differentiation and proliferation. (B) When BRAFV600E mutation occurs it will increase the activation of MEK and ERK which induce a more higher cancer cell proliferation. (C) The treatment which a given BRAF-inhibitor will reduce the increased activation of MEK (and consequently of ERK) by BRAFV600E mutation reducing also tumor cell proliferation.

Figure 2

Panel (A) Representation of the immunosuppressive microenvironment showed in BRAF mutated cancer. The presence of BRAF V600E mutation favors cancer growth and inhibits the patients immunological response. In detail: a) regulatory T cells (Tregs) infiltration is increased b) Mesenchymal derived stromal cells (MDSC) infiltration is increased c) CD8+ T lymphocytes infiltration is reduced d) Dendritic cells infiltration and function is reduced e) Protumorigenic chemokines CCL2 and CXCL8 secretion is increased f) differentiation agents surface expression is reduced g) PDL1 PDL2 surface expression is increased h) MHC Class I-II surface expression is reduced. Panel (B): BRAF mutated cancer immunosuppressive microenvironment can be reverted by treatment with BRAF-inhibitors. In detail: a) regulatory T cells (Tregs) infiltration is reduced b) Mesenchymal derived stromal cells (MDSC) infiltration is reduced c) CD8+ T lymphocytes infiltration is increased d) Dendritic cells infiltration and function is increased e) Protumorigenic chemokines CCL2 and CXCL8 secretion is reduced f) Differentiation agents surface expression is increased g) PDL1 PDL2 surface expression in reduced h) MHC Class I-II surface expression is increased.

Figure 3. Schematic description of the direct and indirect effects of a given BRAF-inhibitor (PLX4720) in cancer.

The presence of the BRAFV600e mutation in cancer cells leads to an increase in cell proliferation, metastasis and patients mortality. The administration of the BRAF-inhibitor PLX4720 exert both direct and indirect effect in cancer. Direct effect: PLX4720 inhibits the molecular pathway switched on by the BRAFV600e mutation, consequently cell proliferation, metastasis and patients mortality are reduced; Indirect effect: PLX4720 inhibits the secretion of pro-tumorigenic chemokines in normal surrounding and cancer cells, which in turn, leads to a reduction of cell proliferation, tumor angiogenesis, EMT and metastatic potential.