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

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.

Exploring the Expression of the «Dark Matter» of the Genome in Mesothelioma for Potentially Predictive Biomarkers for Prognosis and Immunotherapy

“…H3K9me3 is deposited on ERVs by the SETDB1/KAP1 complex (KAP1 is also known as TRIM28) [63] (Figure 2a). Of note in the mesothelioma TCGA patients, the quartile with the lowest KAP1 expression has improved overall survival compared with the patients in the higher quartile Of note in the mesothelioma TCGA patients, the quartile with the lowest KAP1 expression has improved overall survival compared with the patients in the higher quartile [64]. It would be interesting to learn whether this is associated with any change in ERV expression.…”