Discussion

The incidence of melanoma is growing rapidly, cutaneous malignant melanoma being the 5th most common cancer in the UK (2011), accounting for 4% of all new cases and the commonest cancer amongst young adults aged 15-34. Early surgical removal of primary tumours is an effective treatment, but patients that go on to develop metastatic disease have a very poor prognosis and there is no effective therapy for metastatic melanoma.

Chemotherapeutics, such as cisplatin, which are effective against a range of other cancers, are ineffective against melanoma. Bulky lesions affecting one strand of the DNA double helix that are caused by cisplatin, or a variety of other DNA damaging agents, are repaired by the nucleotide excision repair (NER) pathway. ERCC1 is essential for NER and, in the key part of the pathway the XPA protein recognises the DNA lesion and, through an interaction with ERCC1, serves to position a heterodimer of ERCC1 and XPF at the lesion site. The endonuclease domain of XPF then cuts to one side of the lesion leading to its subsequent removal and repair synthesis. ERCC1 is elevated and is a good indicator of poor prognosis in ovarian and lung cancer. ERCC1 has recently been shown to be essential for melanoma growth and resistance to cisplatin in a xenograft model (Song et al., 2011).

Inhibition of ERCC1/XPF may enhance the effectiveness of cisplatin in resistant tumours. We have identified compounds from different chemical series which target the endonuclease activity of XPF and have developed cell based assays to investigate efficacy of these compounds in melanoma and ovarian cell lines. The cell based assays are a recombinant GFP-ERCC1 fluorescent reporter assay, a cisplatin enhancement cell viability assay and also a high content imaging assay to quantify the DNA repair pathway engagement by imaging levels of phospho gamma H2AX in cancer cell lines. Efficacy data will be presented from the cell based assays and correlated with potency in the ERCC1/XPF recombinant assay.

Song L, Ritchie AM, McNeil EM, Li W, Melton DW, (2011) Identification of DNA repair gene Ercc1 as a novel target in melanoma. Pigment Cell Melanoma Research, 24(5), 966-71, 2011