Abstract 3149: Targeting ERBB2-induced, lysosome-mediated invasion

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA ErbB2 overexpression is strongly associated with invasive cancer with high recurrence and poor prognosis. Similarly, increased expression of lysosomal proteases, cysteine cathepsins, is observed in several cancers and correlates with enhanced angiogenesis, invasion and metastasis. We recently showed that ErbB2 level correlates positively with cysteine cathepsin B and L levels in primary breast cancer and that ErbB2 regulates the expression of cathepsins B and L leading to their increased activity in several ErbB2-positive breast cancer cell lines. The increased cysteine cathepsin activity is essential for the invasion of ErbB2 overexpressing breast cancer cells in 3-dimensional (3D) Matrigel cultures and is mediated by novel signaling network that involves TGFβR, ERK2-MAPK, PAK4, PKCα and CDC42bpβ kinases and two transcription factors, MZF1 and ETS1. With a pharmacological protein kinase inhibitor screen, using the ErbB2 inhibitor Lapatinib as positive control, we have now identified three inhibitors putatively targeting this novel ErbB2-induced signaling network. Our data shows that the treatment of ErbB2-positive, highly invasive breast or ovarian cancer cells with any of these inhibitors specifically reduces cysteine cathepsin expression, activity and invasion of these cancer cells in 3D Matrigel cultures. It also reverses lysosomal distribution from the invasion supporting pericellular position to less-invasive perinuclear position, where the lysosomal exocytosis and secretion of lysosome contents to extracellular space to assist extracellular matrix proteolysis becomes less likely. In this study we have identified novel inhibitors for ErbB2-induced invasion and discovered a novel, function for clinically used ErbB2 inhibitor Lapatinib in the regulation of lysosomal function and trafficking. Citation Format: Tuula Kallunki, Ditte M. Brix, Bo Rafn, Knut Kristoffer Bundgaard Clemmensen, Sofie Hagel Andersen, Noona Ambartsumian, Marja Jaattela. Targeting ERBB2-induced, lysosome-mediated invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3149. doi:10.1158/1538-7445.AM2014-3149