KAP1 is a new non-genetic vulnerability of malignant pleural mesothelioma (MPM)

Our plain-English summary of KAP1 is a new non-genetic vulnerability of malignant pleural mesothelioma (MPM), by E. Lorenzini, F. Torricelli, R. Zamponi, et al (NAR Cancer, 2022).

The study

• Authors: E. Lorenzini, F. Torricelli, R. Zamponi, B. Donati, V. Manicardi, E. Sauta, I. Faria do Valle, F. Reggiani, M. Gugnoni, G. Manzotti, V. Fragliasso, E. Vitale, S. Piana, V. Sancisi, A. Ciarrocchi
• Journal: NAR Cancer
• Published: 2022;4(3):zcac024
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare and incurable cancer, which incidence is increasing in many countries. MPM escapes the classical genetic model of cancer evolution, lacking a distinctive genetic fingerprint. Omics profiling revealed extensive heterogeneity failing to identify major vulnerabilities and restraining development of MPM-oriented therapies. Here, we performed a multilayered analysis based on a functional genome-wide CRISPR/Cas9 screening integrated with patients molecular and clinical data, to identify new non-genetic vulnerabilities of MPM. We identified a core of 18 functionally-related genes as essential for MPM cells. The chromatin reader KAP1 emerged as a dependency of MPM. We showed that KAP1 supports cell growth by orchestrating the expression of a G2/M-specific program, ensuring mitosis correct execution. Targeting KAP1 transcriptional function, by using CDK9 inhibitors resulted in a dramatic loss of MPM cells viability and shutdown of the KAP1-mediated program. Validation analysis on two independent MPM-patients sets, including a consecutive, retrospective cohort of 97 MPM, confirmed KAP1 as new non-genetic dependency of MPM and proved the association of its dependent gene program with reduced patients' survival probability. Overall these data: provided new insights into the biology of MPM delineating KAP1 and its target genes as building blocks of its clinical aggressiveness.

© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer.

In plain English

This laboratory study of malignant pleural mesothelioma (MPM), which also analyzed patient data, did not examine asbestos exposure as a risk factor. The authors ran a genome-wide CRISPR/Cas9 gene-knockout screen in the MPM cell line MSTO-211H. They identified 233 genes the cells needed, confirmed using a public database. In 87 TCGA patients, higher expression of 18 of these genes showed the strongest link to shorter survival. For KAP1, patients in the lowest expression quarter had median survival of 43 months, versus 11 months in the highest quarter. Silencing KAP1 in two MPM cell lines reduced growth, increased cell death and disrupted cell-division genes. A CDK9-blocking drug, AZD4573, was toxic to these cells at very low concentrations. In a retrospective cohort of 97 consecutive MPM patients from Reggio Emilia, Italy, 86 had usable samples; among these 86, 67 had professional asbestos exposure recorded. In this cohort, KAP1 and most of its target genes were associated with reduced survival. The authors concluded that KAP1 is a new non-genetic vulnerability in MPM. They called the drug evidence very preliminary and noted both cell lines lacked BAP1 mutations.

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: Laboratory (cell line) study using a genome-wide CRISPR/Cas9 knockout screen and follow-up experiments, combined with analysis of gene expression and survival in a public patient dataset (TCGA) and a retrospective patient cohort
• Who was studied: MPM cell lines MSTO-211H and NCI-H2052. Patient data came from two sources. The first was the TCGA MPM dataset (87 patients; 71 eligible for the validation analysis). The second was a retrospective cohort of 97 consecutive MPM patients from the Pathology Unit of Azienda USL-IRCCS di Reggio Emilia, Italy, collected 2010 to 2021, of whom 86 samples met RNA quality standards.
• Exposure: Asbestos exposure was not an analyzed variable, and no fiber types are named. The study's experimental factors were loss of the KAP1 gene and treatment with CDK inhibitors (AT7519 and AZD4573). Asbestos exposure was recorded only as a clinical feature of the 86 patients with usable samples: professional 67 (77.9%), domestic 8 (9.3%), none 7 (8.1%), missing 4 (4.7%).
• Main results:
  • In the MSTO-211H screen, 457 MPM essential genes were identified after exclusions. Of these, 233 were confirmed using DEPMAP data from seven MPM cell lines.
  • In the TCGA MPM dataset (n = 87), expression of 51 of the 233 genes was associated with reduced survival (P less than 0.05). Of these, 18 showed the strongest association (q less than 0.1).
  • In TCGA patients compared by first versus fourth quartile of KAP1 expression, low-KAP1 patients had a median survival of 43 months and high-KAP1 patients 11 months (OR 6.3).
  • Silencing KAP1 in the MSTO-211H and NCI-H2052 cell lines significantly reduced cell proliferation. It also caused a loss of colony-forming ability and a significant increase in apoptosis (cell death).
  • Loss of KAP1 in MSTO-211H/Cas9 cells significantly changed the expression of 607 genes: 277 down and 330 up. Of the downregulated genes, 90 of 277 were cell cycle genes, and 75 of those 90 were involved in mitosis.
  • The CDK9 inhibitor AZD4573 was toxic to MPM cells at very low concentrations. The EC50 was 23 nM in MSTO-211H cells and 22.9 nM in NCI-H2052 cells.
  • In patient validation, 97.3% (MPM-TCGA dataset) and 86.5% (MPM-RE cohort) of the investigated genes (KAP1 and its targets) showed negative prognostic value. KAP1 itself was associated with reduced survival in both cohorts.
  • In the MPM-RE cohort, 11 of the remaining 17 essential genes from the screen were significantly associated with reduced survival.
• The authors' conclusion: The authors concluded that KAP1 is a new non-genetic vulnerability in MPM, linked to a role in timing the expression of cell-division (G2/M) genes. They described the evidence on CDK inhibitors as very preliminary.
• Limitations the authors state:
  • All experiments were conducted in two cell lines that are not BAP1 mutated.
  • No genetic signature explaining dependence on KAP1 was found, so KAP1 may be a vulnerability only in specific subsets of MPM patients.
  • The evidence on CDK inhibitors as a treatment approach is very preliminary and comes from cell lines.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma.

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