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Background: Mesothelioma, a cancer caused by asbestos is lethal and lacks molecularly targeted therapy. The tumor suppressor NF2 constitutes a frequent, positively selected somatic alteration warranting synthetic lethal approaches to target this driver. NF2 inactivation drives nuclearization of YAP to mediate TEAD dependent oncogenic transcriptional program. YAP is stabilized by CDK7 through phosphorylation of S169/S128/S90, inhibiting the E3 ligase complex CDL4DCAF12. We hypothesized that biallelic NF2 inactivation would be vulnerable to augmentation of CRL4DCAF12 through inhibition of CDK7. Methods: 50 Patients (the MEDUSA cohort) undergoing routine extended pleurectomy decortications consented to have multiregional sampling of their mesotheliomas at resection at 4-5 stereotyped locations, followed by multiregional whole exome sequencing (mWES 200x), phylogenetic deconvolution and transfer learning to examine evolutionary trajectories. Bulk RNA sequencing enabled gene set enrichment analysis, and spatial YAP phenotyping using tissue microarrays were conducted on the mWES profiled cohort. Primary cell lines were generated from a subset of mesotheliomas and whole exome sequenced. Results: NF2 exhibited biallelic inactivation involving copy number/mutation allelic heterogeneity in 42% of mesotheliomas. Double hits were predominantly clonal. Hippo signalosome exhibited additional clonal somatic alterations in 26% of mesotheliomas, with biallelic inactivation being observed in LATS2 (8%) and LATS1 (4%). Transfer learning identified NF2 inactivation as a predominantly secondary clonal event, constituting an evolutionary bottleneck. Random forest analysis revealed YAP dependent transcription, epithelial mesenchymal transition and spindle checkpoint transcriptional signature enrichments in NF2 double hit mesotheliomas. We conducted drug screening of NF2 wild type versus inactivated primary mesothelioma cell lines, which revealed selective sensitivity to CDK7 inhibitors THZ1 and YKL-5-124 in NF2 inactivated but not wild type MEDUSA cell lines. Conclusions: NF2 biallelic inactivation constitutes an evolutionary bottleneck during early mesothelioma evolution, associated with a specific vulnerability to CDK7 highlighting a potential path to clinical stratified therapy. Citation Format: Essa Y. Baitei, Min Zhang, Qianqian Sun, Jin-Li Luo, Philip Zhang, Tamihiro Kamata, James Harber, Aleksandra Bzura, Peter W. Jordan, Charlotte Poile, Alan Dawson, Apostolos Nakas, Cathy Richards, Hongji Yang, Ed Hollox, Dean A. Fennell. Clonal biallelic inactivation of NF2 is an evolutionary bottleneck that exposes a vulnerability to CDK7 inhibition in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6086. |
