Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma.

Autor:	Anobile DP; Department of Oncology, University of Torino, 10043 Orbassano, Italy., Bironzo P; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Thoracic Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino, 10043 Orbassano, Italy., Picca F; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Center for Experimental Research and Medical Studies (CeRMS), City of Health and Science University Hospital di Torino, University of Torino, 10126 Torino, Italy., Lingua MF; Department of Medical Sciences, University of Torino, 10126 Torino, Italy., Morena D; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Center for Experimental Research and Medical Studies (CeRMS), City of Health and Science University Hospital di Torino, University of Torino, 10126 Torino, Italy., Righi L; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Pathology Unit, San Luigi Hospital, University of Torino, 10043 Orbassano, Italy., Napoli F; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Pathology Unit, San Luigi Hospital, University of Torino, 10043 Orbassano, Italy., Papotti MG; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Pathology Unit, City of Health and Science University Hospital, 10126 Torino, Italy.; Interdepartmental Centre for Studies on Asbestos and Other Toxic Particulates, University of Torino, 10125 Torino, Italy., Pittaro A; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Pathology Unit, City of Health and Science University Hospital, 10126 Torino, Italy., Di Nicolantonio F; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Italy., Gigliotti C; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Italy., Bussolino F; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Interdepartmental Centre for Studies on Asbestos and Other Toxic Particulates, University of Torino, 10125 Torino, Italy.; Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Italy., Comunanza V; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Candiolo Cancer Institute-FPO, IRCCS, 10060 Candiolo, Italy., Guerrera F; Department of Surgical Science, University of Torino, 10126 Torino, Italy.; Department of Thoracic Surgery, City of Health and Science University Hospital, 10126 Torino, Italy., Sandri A; Thoracic Surgery Division, San Luigi Hospital, University of Torino, 10043 Orbassano, Italy., Leo F; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Thoracic Surgery Division, San Luigi Hospital, University of Torino, 10043 Orbassano, Italy., Libener R; Department of Integrated Activities Research and Innovation, Azienda Ospedaliera SS. Antonio e Biagio e Cesare Arrigo, 15121 Alessandria, Italy., Aviles P; Research and Development Department, PharmaMar, 28770 Colmenar Viejo, Madrid, Spain., Novello S; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Thoracic Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino, 10043 Orbassano, Italy., Taulli R; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Center for Experimental Research and Medical Studies (CeRMS), City of Health and Science University Hospital di Torino, University of Torino, 10126 Torino, Italy., Scagliotti GV; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Thoracic Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino, 10043 Orbassano, Italy.; Interdepartmental Centre for Studies on Asbestos and Other Toxic Particulates, University of Torino, 10125 Torino, Italy., Riganti C; Department of Oncology, University of Torino, 10043 Orbassano, Italy.; Interdepartmental Centre for Studies on Asbestos and Other Toxic Particulates, University of Torino, 10125 Torino, Italy.; Interdepartmental Research Center of Molecular Biotechnology, University of Torino, 10126 Torino, Italy.
Jazyk:	angličtina
Zdroj:	Cancers [Cancers (Basel)] 2021 May 12; Vol. 13 (10). Date of Electronic Publication: 2021 May 12.
DOI:	10.3390/cancers13102332
Abstrakt:	Background: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer generally diagnosed at an advanced stage and characterized by a poor prognosis. The absence of alterations in druggable kinases, together with an immune-suppressive tumor microenvironment, limits the use of molecular targeted therapies, making the treatment of MPM particularly challenging. Here we investigated the in vitro susceptibility of MPM to lurbinectedin (PM01183), a marine-derived drug that recently received accelerated approval by the FDA for the treatment of patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. Methods: A panel of primary MPM cultures, resembling the three major MPM histological subtypes (epithelioid, sarcomatoid, and biphasic), was characterized in terms of BAP1 status and histological markers. Subsequently, we explored the effects of lurbinectedin at nanomolar concentration on cell cycle, cell viability, DNA damage, genotoxic stress response, and proliferation. Results: Stabilized MPM cultures exhibited high sensitivity to lurbinectedin independently from the BAP1 mutational status and histological classification. Specifically, we observed that lurbinectedin rapidly promoted a cell cycle arrest in the S-phase and the activation of the DNA damage response, two conditions that invariably resulted in an irreversible DNA fragmentation, together with strong apoptotic cell death. Moreover, the analysis of long-term treatment indicated that lurbinectedin severely impacts MPM transforming abilities in vitro. Conclusion: Overall, our data provide evidence that lurbinectedin exerts a potent antitumoral activity on primary MPM cells, independently from both the histological subtype and BAP1 alteration, suggesting its potential activity in the treatment of MPM patients.
Databáze:	MEDLINE
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