Old Targets – New Angles: Targeting mevalonate and VEGF-A pathways in melanoma treatment

Abstract

Background: New therapeutics is urgently needed by those melanoma patients who do not benefit from the current treatment. This thesis uses two approaches to find therapies for these patients: (1) using oncology drugs in a new combinatorial way and (2) using drugs that have not yet been classified as oncology drugs with the new purpose for cancer treatment. Methods: We first characterised a panel of 102 NZM melanoma cell lines derived from metastatic melanoma patients in New Zealand. We then investigate the effects of 3 different statins in these NZM cell lines using genome-scale CRISPR-Cas9 knockout screens to define mechanisms by which statins affected the melanoma cells. Finally, we examined the potential for synergy between VEGFR and BRAF in the growth of melanoma tumours and if this link could be targeted to improve the treatment efficacy. Results: The mutational landscape of NZM cell line panel is representative of what has been observed in melanoma patients in term of the major drivers BRAF, NRAS and NF1 and the deletion of tumours suppressors such as PTEN and CDKN2A. Melanoma cells were particularly sensitive to statins, including BRAF mutant and BRAF WT cells. The studies identified molecular mechanisms of resistance to statins involving multiple genes, including CAB39, KDM6A and MBTPS2. Importantly, the combination of simvastatin and vemurafenib overcame vemurafenib resistance. Next, we identified a link between BRAF and VEGFR which was essential to the growth of melanoma tumours. Strikingly, co-inhibition of BRAF and VEGFR with vemurafenib and axitinib suppressed the growth of BRAF mutant and BRAF WT melanoma tumours. Whole transcriptome analyses revealed synthetic lethality occurring in the combination group with upregulation of TP53 and downregulation of EMT in iv melanoma cells and downregulation of angiogenesis and TGF-beta pathways in the stromal cell population. Conclusions: NZM lines are very representative of melanomas in patients in terms of mutational spectrum and drug responses. The combination of VEGFR and BRAF inhibitors synergistically suppressed the growth of BRAF mutant and BRAF WT melanoma tumours. And, finally, statins strongly inhibited the growth of NZM cells in a multiple-gene mechanism. Clinical evaluation of these findings is warranted.