title: Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab.
abstract: ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90) are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only.
authors.affiliation: Institute of Pathology, Oslo University Hospital, Rikshospitalet University of Oslo, Oslo 0027, Norway. espsta@rr-research.no.
authors.forename: Juliana Bentes
authors.initials: JB
authors.lastname: Hughes
authors.forename: Marianne Skeie
authors.initials: MS
authors.lastname: Rødland
authors.forename: Max
authors.initials: M
authors.lastname: Hasmann
authors.forename: Inger Helene
authors.initials: IH
authors.lastname: Madshus
authors.forename: Espen
authors.initials: E
authors.lastname: Stang