Ex vivo assessment of efficacy of targeted therapies for treatment of HER2-positive parotid gland cancer
Lewandowski, Laura (2019-04-09)
Ex vivo assessment of efficacy of targeted therapies for treatment of HER2-positive parotid gland cancer
(09.04.2019)
Julkaisu on tekijänoikeussäännösten alainen. Teosta voi lukea ja tulostaa henkilökohtaista käyttöä varten. Käyttö kaupallisiin tarkoituksiin on kielletty.
suljettu
Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2019050814833
https://urn.fi/URN:NBN:fi-fe2019050814833
Tiivistelmä
HER2 (human epidermal growth factor receptor 2) positive salivary gland carcinomas are extremely rare with incidence lower than 1 % of all cancers worldwide. Unlike other salivary gland neoplasms, HER2+ salivary gland carcinomas are aggressive and highly invasive malignancies. Due to aggressiveness of the disease and the lack of research material additional research is needed. The aim of this study was to detect the efficacy of HER2-targeted therapies against HER2+ patient derived parotid gland carcinoma cell line in presence of HER3 ligand neuregulin-1β.
Experiment included 19 small-molecular drugs and three antibody-based therapeutics used alone and in combinations. The focus of this study was on lapatinib because certain HER2+ cell lines are known to acquire resistance to it. Neuregulin-1β may have a role in formation of resistance to lapatinib and thus combinations of lapatinib and monoclonal therapeutic anti-HER2 antibodies were screened to study if the resistance could be overcome. The effects of the drugs and neuregulin-1β on cell viability and HER2/AKT-signalling pathway activities were detected by using nuclear staining and reverse-phase protein arrays (RPPAs).
In presence of neuregulin-1β the parotid gland cells did maintain the viability despite increasing concentration of lapatinib. HER2/AKT-signalling activity survey revealed that the resisting effect caused by neuregulin-1β was observed as maintained AKT-activity. HER2-activity in turn was not upregulated. However, a combination of lapatinib and monoclonal therapeutic anti-HER2 antibody pertuzumab inhibited the AKT-activity. These findings support the hypothesis that neuregulin-1β may drive resistance to lapatinib in HER2+ salivary gland carcinoma cells but the effect could be overcome with an antibody-based combination. Exact resistance mechanisms remain somehow unrevealed but the possibility of activation of compensatory signalling routes and structural changes of HER2 molecule are represented to be behind the phenomenon. Further research concerning the activity of bypassing signalling routes is needed to unravel the mechanistic base and thus enhance therapeutic potential.
Experiment included 19 small-molecular drugs and three antibody-based therapeutics used alone and in combinations. The focus of this study was on lapatinib because certain HER2+ cell lines are known to acquire resistance to it. Neuregulin-1β may have a role in formation of resistance to lapatinib and thus combinations of lapatinib and monoclonal therapeutic anti-HER2 antibodies were screened to study if the resistance could be overcome. The effects of the drugs and neuregulin-1β on cell viability and HER2/AKT-signalling pathway activities were detected by using nuclear staining and reverse-phase protein arrays (RPPAs).
In presence of neuregulin-1β the parotid gland cells did maintain the viability despite increasing concentration of lapatinib. HER2/AKT-signalling activity survey revealed that the resisting effect caused by neuregulin-1β was observed as maintained AKT-activity. HER2-activity in turn was not upregulated. However, a combination of lapatinib and monoclonal therapeutic anti-HER2 antibody pertuzumab inhibited the AKT-activity. These findings support the hypothesis that neuregulin-1β may drive resistance to lapatinib in HER2+ salivary gland carcinoma cells but the effect could be overcome with an antibody-based combination. Exact resistance mechanisms remain somehow unrevealed but the possibility of activation of compensatory signalling routes and structural changes of HER2 molecule are represented to be behind the phenomenon. Further research concerning the activity of bypassing signalling routes is needed to unravel the mechanistic base and thus enhance therapeutic potential.