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Dis Model Mech. 2016 Dec 1;9(12):1461-1471. Epub 2016 Oct 20.

Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models.

Author information

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, Colmenar Viejo, Madrid 28770, Spain.
3
Centro Nacional de Investigaciones Oncológicas (CNIO), Calle de Melchor Fernandez Almagro, 3, Madrid 28029, Spain.
4
IRCCS Istituto Clinico Humanitas, via Manzoni 56, Rozzano, Milano 20089, Italy.
5
Department of Research and Development (R&D), PharmaMar S.A, Av. de los Reyes, 1, Colmenar Viejo, Madrid 28770, Spain paviles@pharmamar.com.

Abstract

We explored whether the combination of lurbinectedin (PM01183) with the antimetabolite gemcitabine could result in a synergistic antitumor effect in pancreatic ductal adenocarcinoma (PDA) mouse 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 grooves, inhibiting active transcription and DNA repair; and (ii) specific depletion of tumor-associated macrophages (TAMs). We evaluated the in vivo antitumor activity of lurbinectedin and gemcitabine as single agents and in 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 [combination index (CI)=0.66] and SW-1990 (CI=0.80) tumor xenografts. It also induced complete tumor remissions in four out of six 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 TAM depletion leading to cytidine deaminase (CDA) downregulation in PDA tumors. This effect could, in turn, induce an increase of gemcitabine-mediated DNA damage that was especially relevant in high-density TAM tumors. These results show that lurbinectedin can be used to develop 'molecularly targeted' combination strategies.

KEYWORDS:

Gemcitabine; Lurbinectedin; PDA mouse models; Synergism; Tumor-associated macrophage depletion

Conflict of interest statement

P.Av., C.C., C.M.G. and M.J.G. are employees and shareholders of PharmaMar, SA (Madrid, Spain). No potential conflicts of interest were disclosed by the other authors.

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