Lurbinectedin induces depletion of tumor-associated macrophages (TAM), an essential component of its in vivo synergism with gemcitabine

Author:

Céspedes María Virtudes1,Guillén María José2,López-Casas Pedro Pablo3,Sarno Francesca3,Gallardo Alberto1,Álamo Patricia1,Cuevas Carmen2,Hidalgo Manuel3,Galmarini Carlos María2,Allavena Paola4,Avilés Pablo2,Mangues Ramón1

Affiliation:

1. Institut d'Investigacions Biomèdiques Sant Pau, CIBER de Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN) and Josep Carreras Research Institute, Hospital de Sant Pau, Av. Sant Antoni M. Claret, 167, Barcelona, 08025, Spain

2. Department of Research and Development (R&D), PharmaMar S.A, Av. de los Reyes, 1. 28770, Colmenar Viejo, Madrid, Spain

3. Centro Nacional de Investigaciones Oncológicas (CNIO), Calle de Melchor Fernandez Almagro, 3, 28029 Madrid, Spain

4. IRCCS Istituto Clinico Humanitas, via Manzoni 56, 20089 Rozzano, Milano, Italy

Abstract

We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine may result in synergistic antitumor effect in pancreatic adenocarcinoma (PDA) models. We also studied the contribution of lurbinectedin to this synergism. This drug presents a dual pharmacological effect that contributes to its in vivo antitumor activity: (i) specific binding to DNA minor groove inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs). We evaluated the in vivo antitumor activity of lurbinectedin, gemcitabine (as single agents) and its combination in SW-1990 and MIA PaCa-2 cell-line xenografts and in patient-derived PDA models (AVATAR). Lurbinectedin-gemcitabine combination induced a synergistic effect on both, MIA PaCa-2 (CI=0.66) and SW1990 (CI=0.80) tumor xenografts. It also induced complete tumor remissions in 4 of 6 patient-derived PDA xenografts. This synergism was associated with enhanced DNA damage (anti-γ-H2AX), cell cycle blockage, caspase-3 activation and apoptosis. In addition to the enhanced DNA damage, which is a consequence of the interaction of the two drugs with the DNA, lurbinectedin induced TAMs depletion leading to CDA down-regulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAMs tumors. These results show that lurbinectedin can be used to develop “molecularly-targeted” combination strategies.

Funder

Centre for Industrial Technological Development

Ministerio de Economía y Competitividad

Instituto de Salud Carlos III

European Regional Development Fund

Fundació la Marató de TV3

Agència de Gestió d'Ajuts Universitaris i de Recerca

Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina

Publisher

The Company of Biologists

Subject

General Biochemistry, Genetics and Molecular Biology,Immunology and Microbiology (miscellaneous),Medicine (miscellaneous),Neuroscience (miscellaneous)

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