Review article
The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet?

https://doi.org/10.1016/j.critrevonc.2016.08.011Get rights and content

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleura with a poor prognosis. The most active first-line regimens are platinum compounds and pemetrexed. There is no standard second-line treatment in MPM. Advances in the understanding of tumor molecular biology have led to the development of several targeted treatments, which have been evaluated in clinical trials. Unfortunately none of the explored targeted treatments can currently be recommended as routine treatment in MPM.

We reviewed the biological pathways involved in MPM, the clinical trials about targeted therapy, and possible related mechanisms of resistance. We suggest that specific genetic markers are needed as targets of selective therapy. By this way the selection of patients based on the molecular profile may facilitate a therapeutic strategy that allows the use of the most appropriate drug for each patient.

Introduction

Malignant pleural mesothelioma (MPM) is the most common primary tumor of the pleura, and is related to asbestos exposure in more than 80% of cases (McDonald and McDonald, 1996).

Asbestos, intended as a group of natural crystalline silicates, have been used in various industrial applications (Frank and Joshi, 2014). Occupational exposure to asbestos entails highest risk of asbestos-related diseases. There is no safe level of exposure. Repair, renovation, and demolition of asbestos-containing buildings induces soil contamination and environmental pollution (Marinaccio et al., 2015). Current regulation regards only actinolite, amosite, anthophyllite, chrysotile, crocidolite, and tremolite, but other mineral fibers in the environment, such as erionite has even greater carcinogenic activity and is involved in asbestos-related diseases (Baumann et al., 2013).

Since mineral fibers of asbestos are inhaled, they accumulate in the lungs. A variety of negative effects are developed, such as the production of reactive oxygen species (ROS), chromosome damage, disturbance of mitosis, gene mutations, alteration of growth factor signaling, defects in the apoptotic machinery, deregulation of methylation status, chronic inflammation, phagocytosis, and aberrant microRNA expression (Benedetti et al., 2015). In lung tissue these fibers can cause inflammatory reactions with fibrosis termed as asbestosis. Asbestos bodies accumulate, in the form of fibers coated by iron-containing protein, causing the formation of pleural plaques. Abnormal fluid is collected, and fibers are trapped between the pleural layers. So the wall of the chest cavity induce oxidative stress and chronic inflammation, thus promoting carcinogenesis (Yusa et al., 2015). A cumulative exposure of 25 fibers/year has been estimated to double the risk of lung cancer. About 25% of all cases of malignant mesothelioma are attributed to occupational exposure, 25% to familial exposure, and 50% to environmental exposure (Mensi et al., 2015).

Despite improvements in diagnostic methods and therapeutic strategies, the prognosis of MPM remains poor (12–18 months average survival following diagnosis) except in some exceptional cases (Merritt et al., 2001). For the majority of patients who are not candidate for radical surgical treatment, systemic therapy remains the only valid option.

The first-line therapy for such patients is based on a combination of cisplatin and pemetrexed (Goudar, 2008). Multimodal therapy, which includes extrapleural pneumonectomy or pleurectomy/decortication (with or without radiation therapy), is being studied in selected patients. There are currently no defined standards for second-line therapy (Baas et al., 2015).

A literature search strategy was done using the online databases (Medline – Pubmed, EMBASE, Cochrane Library) for the most updated article on the topic. The keywords were “Mesothelioma”, “Advanced” OR “Metastatic”, “Target therapy”, “PI3K”, “C-MET”, “mTOR”, “FAK”, “HSP”, “PTEN”, “NF-KB”, “Immunotherapy”, and “Resistance” as a free text or through the Medical Subject Headings (MeSH).

Section snippets

Somatic mutations in mesothelioma

The most common somatic mutations in mesothelioma are:

CDK2NA (this gene is altered in about 80% of cases of MPM). There is a loss of Cyclin-Dependent Kinase control with subsequent loss of cellular cycle regulation.

The CDKN2A/ARF (Cyclin-Dependent Kinase Inhibitor 2/Alternative reading frame) gene is also known as p16INK4a/p14ARF and is located on chromosome 9p21. It is an important tumor suppressor gene that codes for two proteins: p16INK4a and p14ARF (Ruas and Peters, 1998, Thillainadesan et

Anti-angiogenic factors

The rationale for using drugs inhibiting this biological pathway arises from the observation that the expression levels of angiogenic factors are increased in MPM patients when compared to healthy subjects. In addition, an increase in VEGF levels is correlated with increased microvessel density and seems to be associated with a poor prognosis (Dowell and Kindler, 2005, Yasumitsu et al., 2010, Klabatsa et al., 2006, Incorvaia et al., 2016, Bronte et al., 2016).

Several anti-VEGF antibodies that

Possible mechanisms of resistance

Even though most of targeted drugs which underwent investigation for MPM failed to provide new therapeutic options, very few has been known about the molecular mechanisms to explain the resistance. The resistance to apoptosis in MPM cells has long been studied to clarify the high frequency of treatment resistance which limits the possibility of survival improvement in MPM patients (Villanova et al., 2008, Mossman et al., 2013). Here we report some of the knowledge about the resistance

Future perspectives

Despite more than two decades of intensive research on the possible treatments for MPM, the results have so far been disappointing. Chemotherapy with cytotoxic drugs is the only treatment that has been proven to improve patients’ outcomes.

A significant contributor to this high failure rate is the lack of reliable pre-clinical models, to evaluate new drugs. The majority of pre-clinical studies for candidate therapeutics are developed in in vitro and in xenograft mouse models. These do not always

Conclusions

In recent years there have been very limited improvements in the systemic treatment of MPM. Currently the only treatment with a clinically significant impact in the survival and quality of life is the chemotherapy combination of cisplatin plus pemetrexed. In the group of patients for whom cisplatin is not indicated, carboplatin may represent a reasonable alternative. Recently the addition of Bevacizumab to cisplatinum-pemetrexed has shown to significantly improve both PFS and OS (Zalcman et

Conflict of interest

The authors have nothing to declare.

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    These authors equally contributed to this work.

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    Both the authors are last name.

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