Melanoma is amongst the top five most common cancers in Australia and the US. Although surgery is effective for treating early stage melanoma, metastatic melanoma remains one of the most difficult cancers to cure. Elevated levels of anti-apoptotic proteins have been demonstrated in virtually every type of human cancers including melanomas. In tumour cells primed for death, pro-apoptotic proteins are bound to anti-apoptotic proteins blocking cell death. BH3 mimetics can interrupt this binding promoting cell death. Several BH3 mimetics have been developed to target the pro-survival proteins BCL-2, BCL-xl, BCL-w and MCL-1. However, there are no such drugs currently available for targeting BFL-1, which in some instances represents a resistance factor for malignancies treated with current BH3 mimetics.
BFL-1 is expressed at very high levels in some melanomas, which is thought to be a key mechanism of resistance to therapies, including mutant BRAF inhibitors. I have screened the BFL-1 expression in a panel of human melanoma cell lines and patient derived xenograft tissues. CRISPR mediated deletion of the BFL-1 gene was carried out in several BRAF mutant melanoma cell lines. These cell lines were then treated either alone or a combination of BH3 mimetics, BRAF inhibitors and MEK inhibitors followed by cell death analysis. Although, BRAF and MEK inhibitors alone did not result in the death of the BFL-1 knockout cells, the combination of these drugs with BH3 mimetics targeting the other BCL-2 proteins resulted in enhanced killing of melanoma cells lacking BFL-1 in comparison to parental cells. This confirms the importance of the development of a BH3 mimetic to target BFL-1.