BRAF/MEK inhibitors promote CD47 expression that is reversible by ERK inhibition in melanoma

Abstract

The expression of CD47 on the cancer cell surface transmits “don’t eat me” signalling that not only inhibits phagocytosis of cancer cells by phagocytes but also impairs anti-cancer T cell responses. Here we report that oncogenic activation of ERK plays an important role in transcriptional activation of CD47 through nuclear respiratory factor 1 (NRF-1) in melanoma cells. Treatment with BRAF/MEK inhibitors upregulated CD47 in cultured melanoma cells and fresh melanoma isolates. Similarly, melanoma cells selected for resistance to the BRAF inhibitor vemurafenib expressed higher levels of CD47. The increase in CD47 expression was mediated by ERK signalling, as it was associated with rebound activation of ERK and co-knockdown of ERK1/2 by siRNA diminished upregulation of CD47 in melanoma cells after exposure to BRAF/MEK inhibitors. Furthermore, ERK1/2 knockdown also reduced the constitutive expression of CD47 in melanoma cells. We identified a DNA fragment that was enriched with the consensus binding sites for NRF-1 and was transcriptionally responsive to BRAF/MEK inhibitor treatment. Knockdown of NRF-1 inhibited the increase in CD47, indicating that NRF-1 has a critical role in transcriptional activation of CD47 by ERK signalling. Functional studies showed that melanoma cells resistant to vemurafenib were more susceptible to macrophage phagocytosis when CD47 was blocked. So these results suggest that NRF-1-mediated regulation of CD47 expression is a novel mechanism by which ERK signalling promotes the pathogenesis of melanoma, and that the combination of CD47 blockade and BRAF/MEK inhibitors may be a useful approach for improving their therapeutic efficacy.

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

“…BRAF inhibitor resistance involves a range of transcription factors ( Table 2 ) [ 14 , 16 , 22 , 28 , 45 , 46 , 48 , 52 , 58 , 66 , 81 , 89 , 97 , 117 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. A transcriptomic analysis of BRAF inhibitor-resistant melanoma cells showed that some transcription factors were upregulated whereas others were downregulated [ 141 ].…”

“…In the tumor cell, this reversion to a low immunogenic state is caused by induced expression of programmed cell death ligand-1 (PD-L1) [ 165 , 166 , 167 , 168 , 169 ], increased expression of the immunoregulatory protein Galactin-1 [ 170 ], and increased expression of CD47, an immunoregulatory cell marker, on tumor cells, leading to reduced killing by cytotoxic T-cells and macrophages [ 133 ]. BRAF inhibitor-resistant tumor cells also show reduced expression of target antigens [ 164 ], and increased production of IL-10 [ 33 ].…”

Ginsenoside G-Rh2 synergizes with SMI-4a in anti-melanoma activity through autophagic cell death

“…Melanoma is the highly aggressive skin cancer with mounting incidence over the past 30 years, which is associated with early metastasis, late diagnosis, and tolerance to chemotherapy in advanced stages [ 1 ]. The emergence of some novel therapies against melanoma such as genetically targeted therapies (e.g., BRAF inhibitors) and immunotherapies (e.g., PD-1/PD-L1 and CTLA-4 antibodies) has undoubtedly improved melanoma treatment, but the overall prognosis of patients remains poor [ 2 , 3 ]. Therefore, it is urgently required to discover novel targets and develop more effective and lasting therapeutic strategies for melanoma.…”

Cardiotoxicity mechanisms of the combination of BRAF-inhibitors and MEK-inhibitors

“…Its activation is subsequent to phosphorylation and relocation from the cytoplasm to the nucleus. (Liu et al, 2017) Studies aiming to understand the role of Thrombospondin-1 (TSP1) have helped in understanding the role played by CD47. TSP1 is a large, secreted glycoprotein.…”