Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

Our plain-English summary of Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight, by D. Xu, H. Yang, R.A. Schmid, et al (Frontiers in Oncology, 2020).

The study

• Authors: D. Xu, H. Yang, R.A. Schmid, R.W. Peng
• Journal: Frontiers in Oncology
• Published: 2020;10:579464
• Type of article: Review
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is the epitome of a recalcitrant cancer driven by pharmacologically intractable tumor suppressor proteins. A significant but largely unmet challenge in the field is the translation of genetic information on alterations in tumor suppressor genes (TSGs) into effective cancer-specific therapies. The notion that abnormal tumor genome subverts physiological cellular processes, which creates collateral vulnerabilities contextually related to specific genetic alterations, offers a promising strategy to target TSG-driven MPM. Moreover, emerging evidence has increasingly appreciated the therapeutic potential of genetic and pharmacological dependencies acquired en route to cancer development and drug resistance. Here, we review the most recent progress on vulnerabilities co-selected by functional loss of major TSGs and dependencies evolving out of cancer development and resistance to cisplatin based chemotherapy, the only first-line regimen approved by the US Food and Drug Administration (FDA). Finally, we highlight CRISPR-based functional genomics that has emerged as a powerful platform for cancer drug discovery in MPM. The repertoire of MPM-specific "Achilles heel" rises on the horizon, which holds the promise to elucidate therapeutic landscape and may promote precision oncology for MPM.

Copyright © 2020 Xu, Yang, Schmid and Peng.

In plain English

This was a review of published laboratory and clinical research on possible drug treatments for malignant pleural mesothelioma (MPM). Asbestos was not studied; the authors noted MPM's association with asbestos exposure and rising global incidence and mortality owing to long latency and continued asbestos use in developing countries. They described possible weak points in tumors lacking tumor suppressor genes, most often CDKN2A, BAP1 and NF2. They also covered dependencies tied to tumor growth and cisplatin resistance, and CRISPR gene screening. A cited phase 3 trial found adding bevacizumab to cisplatin and pemetrexed significantly improved median overall survival. Trials of vorinostat, thalidomide and nintedanib showed no benefit. For FAK inhibitors, a phase 1 study found longer median progression-free survival in patients with NF2-negative than NF2-positive tumors. A later phase II trial found no survival improvement in previously treated patients with NF2-low MPM; the authors called for further study. They noted cell lines used in most screening studies poorly reflect how varied MPM tumors are. The authors concluded that recently identified vulnerabilities may bring hope for biomarker-guided precision medicine for MPM.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research
• Who was studied: Published laboratory and clinical research on malignant pleural mesothelioma. A figure shows tumor-gene mutation data from 87 MPM patient samples in The Cancer Genome Atlas (TCGA).
• Exposure: Not studied. No fiber types are named. The authors described MPM as etiologically associated with asbestos exposure. They also noted that asbestos is banned in most industrialized countries, yet MPM incidence and mortality still increase globally. They attributed this to the disease's long latency (up to 50 years) and continued asbestos use in developing countries. The review itself concerns drug treatments targeting tumor genetic changes.
• Main results:
  • According to the genomic studies the authors cite, the tumor suppressor genes most often lost or inactivated in MPM are CDKN2A, BAP1 and NF2.
  • From cited studies: TP53 is mutated in 6 to 16% of MPM cases, and LATS2 alterations occur in about 11% of MPM patients.
  • From a cited phase 3 trial (MAPS, 448 patients in the authors' table): adding bevacizumab to cisplatin and pemetrexed significantly improved median overall survival in MPM. The table lists overall survival as 18.8 vs. 16.1, with no units stated.
  • From a cited phase 3 trial of more than 600 MPM patients (661 in the authors' table): vorinostat, an HDAC inhibitor, gave disappointing results.
  • From cited randomized phase 3 trials: adding thalidomide, or adding nintedanib, to chemotherapy showed no benefit.
  • From a cited phase 1 study: among patients treated with FAK inhibitors, median progression-free survival was longer in patients with NF2-negative MPM than in those with NF2-positive tumors.
  • From the cited phase II COMMAND trial: FAK inhibitors improved neither progression-free survival nor overall survival in patients with NF2-low MPM who had prior chemotherapy. The authors said further investigation is needed to establish the link between NF2 status and response to FAK inhibition.
  • The authors described their own earlier CRISPR screen of MPM cells. It indicated that deregulated G2-M checkpoint activity governs MPM response to chemotherapy.
• The authors' conclusion: The authors concluded that recently identified vulnerabilities may bring hope for biomarker-guided precision medicine for MPM. These are vulnerabilities linked to faulty tumor suppressor genes, and dependencies acquired during cancer development and drug resistance.
• Limitations the authors state:
  • The authors stated a limitation of the research they reviewed, not of their own review: the cancer cell lines used in most RNAi and CRISPR screening studies poorly reflect the conditions under which varied (heterogeneous) MPM tumors arise and evolve.
  • The authors noted that earlier shRNA screens in MPM surveyed relatively few cell lines, none of which represented the diversity of MPM.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Tumor Suppressor Gene, Cisplatin, Chemotherapy, Discovery.

Related studies

• Systematic Analysis of Aberrant Biochemical Networks and Potential Drug Vulnerabilities Induced by Tumor Suppressor Loss in Malignant Pleural Mesothelioma — H. Yang, D. Xu, et al. (2020)
• De novo pyrimidine synthesis is a collateral metabolic vulnerability in NF2-deficient mesothelioma — D. Xu, Y. Gao, et al. (2025)
• Therapeutic vulnerabilities exposed by the 9p21 loss identified through multiparametric drug screening inform rational combination strategies — R. Bevilacqua, P. Gasperini, et al. (2026)
• Insights Into Genomic Drivers, Transcriptomic Heterogeneity, and Therapeutic Vulnerabilities From Novel Mesothelioma Cell Lines — Y. Wu, F. Cao, et al. (2026)
• Methylation profile landscape in mesothelioma: possible implications in early detection, disease progression, and therapeutic options — X. Zhang, N. Tang, et al. (2015)
• Genomic Landscape of Pleural Mesothelioma and Therapeutic Aftermaths — A. Nash, J. Creaney (2023)

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