Sitzung

64 - Freie Mitteilung
Cancer
16. Mai 2019, 13:45 - 15:15, Szenario 1, 5. OG

Abstract

5
Lysosomal compartment dysregulation as a treatment strategy for hepatocellular carcinoma
J. Gavini1, N. Dommann1, M. Jakob1, A. Keogh1, L. Bouchez2, S. Karkampouna1, M. Kruithof-de Julio1, M. Medova1, Y. Zimmer1, D. Candinas1, D. Stroka1, V. Banz1, Presenter: J. Gavini1 (1Bern, 2Basel)

Ziel
Lysosomal sequestration of anti-cancer compounds reduces drug availability at intracellular target sites, thereby limiting drug-sensitivity and inducing chemoresistance. For hepatocellular carcinoma (HCC), sorafenib (SF) is the first line systemic treatment as well as a simultaneous activator of autophagy-induced drug resistance. The purpose of this study is to elucidate how combination therapy with the FDA-approved photosensitizer verteporfin (VP) can potentiate the antitumor effect of SF, overcoming its acquired resistance mechanisms.
Methoden
HCC cell lines and patient-derived in vitro and in vivo preclinical models were used to identify the molecular mechanism of action of VP alone and in combination with SF.
Resultate
We demonstrate that SF is lysosomotropic and increases the total number of lysosomes in HCC cells and patient-derived xenograft model. Contrary to the effect on lysosomal stability by SF, VP is not only sequestered in lysosomes, but induces lysosomal pH alkalinization, lysosomal membrane permeabilization (LMP) and tumor-selective proteotoxicity. In combination, VP-induced LMP potentiates the antitumor effect of SF, further decreasing tumor proliferation and progression in HCC cell lines and patient-derived samples in vitro and in vivo. We further describe the impact of RAS oncoprotein status on lysosomal compartment stability after LMP.
Schlussfolgerung
Our data suggest that combination of lysosome-targeting compounds, such as VP, in combination with already approved chemotherapeutic agents could open a new avenue to overcome chemo-insensitivity caused by passive lysosomal sequestration of anti-cancer drugs in the context of HCC.
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