Specific inhbitor of ERK 1/2 AEZS-131: anticancer activity in models of human cancers with and without overactivation of ERK 1/2

Purpose: The RAS/RAF/MEK/ERK pathway is activated in more than 30% of human cancers, mostly via mutation in K-Ras oncogene and also via mutations in BRAF. Although various MEK-inhibitors have been developed, acquired resistance to MEK-inhibitors is a major problem. We investigate specific ERK inhibitor AEZS-131 in a panel of human cancers with and without mutations in the MAPK-pathway.

Methods: The ability of AEZS 131 to selectively target cancer cell proliferation and survival is demonstrated in-vitro by MTT-assays and FACS based analysis. Furthermore the mechanism of cytotoxicity is analysed by FACS based assays.

Results: In MDA-MB-435 s cells RSK-1 phosphorylation a downstream target of ERK was reduced by 50% subsequent to treatment with AEZS-131. AEZS-131 effectively inhibited cell growth with IC₅₀ in low mM range in 3 ovarian, 5 breast and 3 endometrial cancer cell lines, of which 2 mammary and 2 endometrial harboured mutations in ERK-pathway. The compound was ineffective in 1 breast and 2 ovarian cancer lines without mutations in ERK-pathway. AEZS-131 dose dependently increased tumour cell lysis by natural killer cells, suggesting potential synergistic effects with the host anti-tumour response.

Conclusion: We could demonstrate good anti-tumour-activity of AEZS-131 in different cancers in-vitro. Cytotoxicity was pronounced in cancers harbouring mutation in MAPK-pathway, but did also occur in some cancer cell lines which are negative for such mutations. As tumours resistant to MEK-inhibitors stay sensitive to inhibition of ERK 1/2, AEZS-131 should be further evaluated in in-vivo studies, in particular in tumours harbouring a mutation in ERK-pathway.