Integrated genomics point to immune vulnerabilities in pleural mesothelioma

AbstractPleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

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Multiple therapeutic pathways in malignant mesothelioma identified by genomic mapping

10.1101/2020.01.23.20018523 ◽

2020 ◽

Author(s):

Anca Nastase ◽

Amit Mandal ◽

Shir Kiong Lu ◽

Hima Anbunathan ◽

Deborah Morris-Rosendahl ◽

...

Keyword(s):

T Cell ◽

Kinase Inhibitors ◽

Aurora Kinase ◽

Genomic Mapping ◽

Type I ◽

Poor Survival ◽

Aurora Kinase Inhibitors ◽

Primary Cell Lines ◽

Low Passage ◽

Cell Synapse

AbstractMalignant pleural mesothelioma (MPM) is an aggressive malignancy that lacks effective therapy. To identify therapeutic targets we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised losses of SUFU, observed in 21% of 118 tumours, resulted in disordered expression of Hedgehog pathway transcripts and genes from the T-cell synapse, including VISTA. Co-deletion of Interferon type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary MPM cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. The results indicate multiple new therapeutic avenues in MPM and include targets and biomarkers for immunotherapy.Statement of SignificanceWe have discovered previously unreported copy number aberrations in MPM that led us to find micromolar responses of patient-derived primary cell lines to PLK1, CHEK1, Aurora Kinase and YAP1 inhibitors. Deletions of the hedgehog modulator SUFU had marked effects on the expression of T-cell synapse genes, providing a rational basis to VISTA inhibition for MPM immunotherapy.

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Aurora Kinase Inhibitors in Head and Neck Cancer

Current Topics in Medicinal Chemistry ◽

10.2174/1568026618666180112163741 ◽

2018 ◽

Vol 18 (3) ◽

pp. 199-213

Author(s):

Guangying Qi ◽

Jing Liu ◽

Sisi Mi ◽

Takaaki Tsunematsu ◽

Shengjian Jin ◽

...

Keyword(s):

Head And Neck Cancer ◽

Cancer Therapy ◽

Kinase Inhibitors ◽

Biological Function ◽

Aurora Kinase ◽

Aurora Kinases ◽

Related Research ◽

Chemotherapy Drugs ◽

Aurora Kinase Inhibitors

Aurora kinases are a group of serine/threonine kinases responsible for the regulation of mitosis. In recent years, with the increase in Aurora kinase-related research, the important role of Aurora kinases in tumorigenesis has been gradually recognized. Aurora kinases have been regarded as a new target for cancer therapy, resulting in the development of Aurora kinase inhibitors. The study and application of these small-molecule inhibitors, especially in combination with chemotherapy drugs, represent a new direction in cancer treatment. This paper reviews studies on Aurora kinases from recent years, including studies of their biological function, their relationship with tumor progression, and their inhibitors.

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