Co-targeting human mammary cancer cells with kinase- and protease-inhibitors

Abstract: Breast cancer is the most frequent cancer in women. As it is on molecular level a heterogenous disease, clinicians need personalized therapy options. Despite a significant progress in individual targeted therapies with Her2 and estrogen receptor specific drugs, breast cancer is still responsible for 15% of all cancer related deaths in women. Since breast cancer cells develop resistance to the primary chemotherapy, clinicians are lacking satisfying therapy options for relapsed patients.
Around one third of breast cancer patients has an activating mutation in the oncogene PIK3CA. This activates the PI3 kinase pathway – a driver pathway for proliferation in breast cancer. Next to PI3 kinase activity proteases such as ADAMs and cathepsins are also often upregulated in breast cancer cells. They promote proliferation, migration, and invasion via remodeling the extra cellular matrix. As both enzyme classes are strongly connected and both linked to the pathogenesis of breast cancer, this medical thesis aims to outline the clinical potential of simultaneous targeting PI3 kinases and proteases.
Four different human breast cancer cells were treated with the different kinase inhibitors BEZ235 or BKM120 in combination with different protease inhibitors (TAPI-O, E64D, Leupeptin, Pepstatin or Bortezomib). Experiments in various co-targeting combinations were performed to explore cancer cell proliferation and migration. We identified a synergistic cooperation of metalloproteases and PI3 kinases in maintaining proliferation of breast cancer cells. Especially cytokine and receptor shedding from cancer cell surface showed a strong bi-directional interaction between PI3 kinases and metalloproteases. Remarkably, we could demonstrate that the combination of broad-spectrum metalloprotease inhibitor TAPI-O and PI3 kinase inhibitor presents a new approach to overcome resistance or non-responding to Trastuzumab treatment.
As clinical trials with single targeting of proteases or kinases often failed, we propose dual-targeting of metalloproteases and PI3 kinases as a promising concept to be further explored in vivo. The individual metalloproteases responsible for the observed effects remains to be characterized to reduce off target side effects

Objekt anzeigen

• Standort: Deutsche Nationalbibliothek Frankfurt am Main
• Umfang: Online-Ressource
• Sprache: Englisch
• Anmerkungen: Universität Freiburg, Dissertation, 2022

Klassifikation und Themen

• Schlagwort: Protease inhibitors ; Cancer cells ; Brustkrebs ; Phosphatidylinositolkinase ; Proteaseinhibitor ; Metalloproteinaseninhibitor ; Onkogen HER-2/neu

Beteiligte, Orts- und Zeitangaben

• Ereignis: Veröffentlichung
• (wo): Freiburg
• (wer): Universität
• (wann): 2022
• Urheber: Weber, Sophia
• Beteiligte Personen und Organisationen: Reinheckel, Thomas ; Schilling, Oliver ; Albert-Ludwigs-Universität Freiburg. Institut für Molekulare Medizin und Zellforschung ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät

Weitere Informationen

• DOI: 10.6094/UNIFR/223930
• URN: urn:nbn:de:bsz:25-freidok-2239304
• Rechteinformation: Kein Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.