PO-507 ADAM22 as a therapeutic target for endocrine resistant metastatic breast cancer

Abstract

IntroductionThe development of endocrine resistance is a major hurdle for the treatment of oestrogen receptor positive (ER+) breast cancer. One of the key contributors to this resistant phenotype is overexpression of the nuclear receptor coactivator SRC-1, which in turn has been shown to promote metastatic disease. Using CHIP-seq and microarray studies, the neuronal protein ADAM22 (A Disintegrin And Metalloproteinase) was identified as a potential pro-metastatic SRC-1 regulated gene in endocrine resistant cell lines. ADAM22 expression promotes both migration and de-differentiation, key hallmarks of metastasis. While clinically, elevated ADAM22 expression predicts poor disease free survival. Here, both the role of ADAM22 in metastatic development and the clinical potential of ADAM22 as a biomarker and therapeutic target were explored.Material and methodsThe functional effect of ADAM22 modulation on anchorage independent growth and mammosphere formation was investigated using CRISPR/Cas9 knockout and lentiviral overexpression in the endocrine resistant LY2 cell line. To examine the clinical relevance of ADAM22 as a biomarker, ADAM22 expression was examined in matched primary breast and metastatic cancer tissues. A small peptide mimetic of the ADAM22 endogenous ligand LGI1 (LGIMIM) was designed and explored as a potential anti-ADAM22 therapeutic both in vitro and in vivo.Results and discussionsADAM22 expression promotes anchorage independent growth and mammosphere formation, suggesting ADAM22 contributes to both the survival of metastatic cells and their ability to colonise distant sites. ADAM22 expression was significantly higher in primary breast tumours which went on to metastasise versus primaries which did not. A significant increase in ADAM22 expression was found in brain metastatic tissue compared to matched primary tissue, suggesting ADAM22 may prime endocrine resistant cancer cells to colonise the brain. LGIMIM treatment was sufficient to inhibit ADAM22 mediated phenotypes in vitro and to reduce metastatic burden in a xenograft model of endocrine resistance in vivo.ConclusionADAM22 is a promising biomarker and therapeutic target for endocrine resistant breast cancer.