Evaluation of the Preclinical Efficacy of Lurbinectedin in Malignant Pleural Mesothelioma

Abstract

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.

A Glimpse in the Future of Malignant Mesothelioma Treatment

“…Lubrinectedin acts by binding specific DNA sites thus impeding the access of transcriptional machinery and by inhibiting the function of tumor-associated macrophages (Santamaría Nuñez et al, 2016). A preliminary in vitro study showed a high sensitivity of MMe cell lines to Lubrinectidin, regardless of the BAP1 status and histological subtype (Anobile et al, 2021). Specifically, the inhibition in tumor growth was caused by the stop of the cell cycle in the S-phase with the activation of the DNA damage response and consequent apoptotic cell death.…”

Trabectedin and lurbinectedin: Mechanisms of action, clinical impact, and future perspectives in uterine and soft tissue sarcoma, ovarian carcinoma, and endometrial carcinoma

“…Lurbinectedin has significant antitumor efficacy with tolerable AEs in patients with platinum-sensitive and platinum-resistant SCLCs and in those with recurrent SCLCs after second-line treatment, and this agent has been approved by the FDA for patients with metastatic SCLCs with disease progression on or after platinum-based chemotherapy ( 23 , 24 ). Lurbinectedin has also shown activity against malignant pleural mesothelioma ( 25 , 26 ); sarcoma, especially leiomyosarcoma, myxoid liposarcoma, and dedifferentiated liposarcoma ( 22 ); and ovarian ( 27 – 29 ) and endometrial carcinoma ( 29 – 31 ).…”

Malignant Mesothelioma

“…In the search for new targets, Yang et al demonstrated that the exploration of aberrant biochemical networks and potential drug vulnerabilities induced by tumor suppressor loss provide interesting prospects for the treatment of MM [ 16 ]. Moreover, Anobile, Bironzo et al evaluated the preclinical efficacy of a new marine-derived anticancer drug in patient-derived samples of MM [ 17 ]. Finally, Kotecha, Tonse et al provided baseline comparative values in their review of survival of MM patients treated with systemic therapy combinations for locally, advanced, or metastatic disease [ 18 ], and Dulloo et al reviewed new opportunities in molecular strategy therapy for this cancer [ 19 ].…”