Mediating BRAF-mutant melanoma resistance

What is the primary cause of resistance to mitogen-activated protein kinase (MAPK) inhibitors in patients with BRAF-mutant melanoma, and why does it occur mainly through non-mutational events?

The primary cause of resistance to MAPK inhibitors in melanoma is felt to be epigenetic as mutations associated with MAPKi resistance have only been seen in a small percentage of patients. It is not clear why these resistance mechanisms are largely epigenetic although many scientists speculate that the malleable nature of epigenetic events and associated tumour cell plasticity are highly advantageous to the tumour cell.

Regarding therapy resistant melanomas, why is the alteration of the epigenetic landscape considered significant, and what has been lacking in terms of validated targetable epigenetic mechanisms?

The alteration of the epigenetic landscape in terms of therapy-resistance mechanisms in cancers is significant as it shifts the paradigm regarding the therapeutic approach to cancers.  Rather than solely identifying tumour-associated mutations which can be specifically targeted for effective treatment, we now need to consider how non-mutational events play into both the development of the primary tumour and the development of therapy resistance.  It is also enticing to consider how epigenetic approaches may be used to prevent the development of both tumour progression as well as therapy resistance.  In this way, a dual-pronged approach to both genetic and epigenetic changes in cancer is expected to be most successful.

What role does CoREST play in mediating distinct melanoma phenotypes, and how does corin treatment impact the reprogramming of melanoma cell phenotypes?

Our data demonstrate that the CoREST complex is a critical mediator of the distinct melanoma phenotypes, working through the regulation of both the phenotype-defining genes MITF and AXL as well as the master regulators of epithelial-to-mesenchymal transitions (EMT) and phenotype switching in melanoma and other cancers, SNAIL/SLUG/ZEB1/ZEB2.  Amazingly, corin treatment of melanoma cells reverses the resistance-associated phenotypes of either an MITF^hi/AXL^lo or MITF^lo/AXL^hi tumour cell to an intermediate, and non-resistant state.

What outcome is noted when treating BRAF inhibitor (BRAFi)-resistant melanomas with corin?

What is remarkable here is that we show that the addition of corin to BRAFi-resistant tumour cells resensitises them to BRAFi therapies.  This happens both in vitro and in vivo and suggests that a new treatment paradigm for melanoma might include metronomic therapy between a BRAF inhibitor and a CoREST inhibitor in order to prevent the development of therapy-resistant cancers.

How does the study indicate that CoREST inhibitors could benefit patients with BRAFi-resistant melanoma?

As mentioned above, our data suggest that a potential new treatment paradigm for melanoma might include metronomic therapy between a BRAF inhibitor and a CoREST inhibitor in order to prevent the development of therapy-resistant cancers. In addition, it is worth noting that phenotype-switching (EMT) and tumour cell plasticity are features of therapy resistance mechanisms in a large number of other cancers, most notably breast cancers, suggesting that the above paradigm may also be relevant to targeted therapy resistance mechanisms for other cancer types.

This study was published in the Journal of Clinical Investigation.