Splicing deregulation, microRNA and notch aberrations: fighting the three-headed dog to overcome drug resistance in malignant mesothelioma

ABSTRACT

Introduction

Malignant mesothelioma (MMe) is an aggressive rare cancer of the mesothelium, associated with asbestos exposure. MMe is currently an incurable disease at all stages mainly due to resistance to treatments. It is therefore necessary to elucidate key mechanisms underlying chemoresistance, in an effort to exploit them as novel therapeutic targets.

Areas covered

Chemoresistance is frequently elicited by microRNA (miRNA) alterations and splicing deregulations. Indeed, several miRNAs, such as miR-29c, have been shown to exert oncogenic or oncosuppressive activity. Alterations in the splicing machinery might also be involved in chemoresistance. Moreover, the Notch signaling pathway, often deregulated in MMe, plays a key role in cancer stem cells formation and self-renewal, leading to drug resistance and relapses.

Expert opinion

The prognosis of MMe in patients varies among different tumors and patient characteristics, and novel biomarkers and therapies are warranted. This work aims at giving an overview of MMe, with a special focus on state-of-the-art treatments and new therapeutic strategies against vulnerabilities emerging from studies on epigenetics factors. Besides, this review is also the first to discuss the interplay between miRNAs and alternative splicing as well as the role of Notch as new promising frontiers to overcome drug resistance in MMe.

KEYWORDS:

• Chemoresistance
• malignant mesothelioma
• microRNA
• splicing deregulation
• notch
• cancer stem cells
• targeted therapy

Article highlights

• Malignant mesothelioma is a rare and aggressive cancer, characterized by a dismal prognosis, and therapeutic options are limited. Therefore, it is mandatory to identify novel biomarkers and therapeutic targets, to improve prognosis and quality of life.

• Patients treated with the current chemotherapeutic regimen, based on pemetrexed and cisplatin, often develop resistance to treatment.

• Increasing evidence shows the pivotal role that microRNAs and spliceosome deregulation play in tumorigenesis and chemoresistance. Promising results from preclinical and clinical studies point into the direction of novel therapeutic agents targeting this interplay as a way to overcome chemoresistance.

• Similarly, overexpression of Notch signaling pathway has been associated with MMe chemoresistance and cancer stem cells (CSCs) formation, suggesting that Notch inhibition could represent a novel promising targeted therapy.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was supported by Cancer Center Amsterdam (CCA) Foundation grant 2015 (E.G.); Italian Association for Cancer Research (AIRC) IG grant 2020-24444 (E.G.); PON grant from the Italian Ministry of Education, University and Research (C.P., E.G.); ‘the Law Offices of Peter G. Angelos Grant’ from the Mesothelioma Applied Research Foundation (MARF) (E.G.); National Science Centre of Poland (2018/31/B/NZ7/02909) (G.J.P., E.G.); and IDUB (664/256/62-0212) (GJP) European Cooperation in Science and Technology (COST) Action 17104 STRATAGEM (C.R., E.G.).