Evaluation von Anti-HER-2-Substanzen für die Therapie des kolorektalen Karzinoms

Evaluation of targeting HER-2 as a therapeutic strategy in colorectal cancer

by Anna-Lena Clara Metzger
Doctoral thesis
Date of Examination:2020-11-03
Date of issue:2020-09-29
Advisor:PD Dr. Marian Grade
Referee:Prof. Dr. Dieter Kube
Referee:Prof. Dr. Martin Oppermann
Persistent Address: http://dx.doi.org/10.53846/goediss-8226

 

 

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Abstract

English

Abrogation of growth factor-dependent signaling represents an effective therapeutic strategy for patients with colorectal cancer (CRC). Here we evaluated the effectiveness of targeting the epidermal growth factor (EGF) receptor HER-2 in the three cell lines LS513, LS1034 and SW837. Treatment with HER-2-specific antibodies trastuzumab and pertuzumab resulted in a mild reduction of cellular viability. In contrast, the antibody-drug conjugate T-DM1 mediated a strong and dose-dependent decrease of viability and Akt phosphorylation. The most striking effects were observed with the dual tyrosine kinase inhibitor lapatinib, and the Pan-ErbB inhibitor afatinib. Selectively, the effect of EGF receptor inhibition was augmented by a combination with 5fluorouracil and oxaliplatin. In conclusion, inhibition of EGF receptors effectively blocks downstream signaling and significantly impairs viability of CRC cells. However, the effectiveness of receptor inhibition highly depends on the inhibitors’ mode of action, as targeting HER-2 alone is not sufficient. Since HER-2 is expressed in a relevant number of patients, targeting this receptors may represent a promising therapeutic strategy for CRC.
Keywords: Colorectal cancer; HER-2; Targeted therapy; Inhibitors
Schlagwörter: Kolorektales Karzinom; zielgerichtete Therapie; HER-2
 
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