Dataset Information

Deubiquitinase Vulnerabilities Identified through Activity Based Protein Profiling in Non-Small Cell Lung Cancer

ABSTRACT: To aid in the prioritization of deubiquitinases (DUBs) as anticancer targets, we developed an approach combining activity-based protein profiling (ABPP) with mass spectrometry in both non-small cell lung cancer (NSCLC) tumor tissues and cell lines along with analysis of available RNA interference and CRISPR screens. We identified 67 DUBs in NSCLC tissues, 17 of which were overexpressed in adenocarcinoma or squamous cell histologies, and 12 scoring as affecting lung cancer cell viability in RNAi or CRISPR screens. We used the CSN5 inhibitor, which targets COPS5/ CSN5, as a tool to understand the biological significance of one of these 12 DUBs, COPS6, in lung cancer. Our study provides a powerful resource to interrogate the role of DUB signaling biology and nominates druggable targets for the treatment of lung cancer subtypes.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: John Koomen

LAB HEAD: Eric Haura

PROVIDER: PXD028802 | Pride | 2022-07-05

REPOSITORIES: Pride

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Publications

Deubiquitinase Vulnerabilities Identified through Activity-Based Protein Profiling in Non-Small Cell Lung Cancer.

Mahajan Shikha S Majumder Anurima A Stewart Paul A PA Chen Yian Ann YA Adhikari Emma E Fang Bin B Yang Yan Y Lawrence Harshani H Kinose Fumi F Koomen John M JM Haura Eric B EB

ACS chemical biology 20220321 4

To aid in the prioritization of deubiquitinases (DUBs) as anticancer targets, we developed an approach combining activity-based protein profiling (ABPP) with mass spectrometry in both non-small cell lung cancer (NSCLC) tumor tissues and cell lines along with analysis of available RNA interference and CRISPR screens. We identified 67 DUBs in NSCLC tissues, 17 of which were overexpressed in adenocarcinoma or squamous cell histologies and 12 of which scored as affecting lung cancer cell viability i ...[more]

PMID: 35311290

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Project description:The purpose of this study was to identify molecular markers of pathologic response to neoadjuvant paclitaxel/radiation treatment, protein and gene expression profiling were done on pretreatment biopsies. Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel followed by concurrent paclitaxel/radiation. Tumor tissue from pretreatment biopsies was obtained from 19 of the 38 patients enrolled in the study. Protein and gene expression profiling were done on serial sections of the biopsies from patients that achieved a pathologic complete response (pCR) and compared to those with residual disease, non-pCR (NR). Proteomic and validation immunohistochemical analyses revealed that Î±-defensins (DEFA) were overexpressed in tumors from patients with a pCR. Gene expression analysis revealed that MAP2, a microtubule-associated protein, had significantly higher levels of expression in patients achieving a pCR. Elevation of MAP2 in breast cancer cell lines led to increased paclitaxel sensitivity. Furthermore, expression of genes that are associated with the basal-like, triple-negative phenotype were enriched in tumors from patients with a pCR. Analysis of a larger panel of tumors from patients receiving presurgical taxane-based treatment showed that DEFA and MAP2 expression as well as histologic features of inflammation were all statistically associated with response to therapy at the time of surgery. We show the utility of molecular profiling of pretreatment biopsies to discover markers of response. Our results suggest the potential use of immune signaling molecules such as DEFA as well as MAP2, a microtubule-associated protein, as tumor markers that associate with response to neoadjuvant taxaneâbased therapy. Tumor tissues from pretreatment needle biopsies from patients enrolled on a paclitaxel/radiation clinical trial were laser capture microdissected for RNA extraction and hybridization to Affymetrix microarrays. We analyzed one array (sample A) from duplicate samples from each patient. 14 subject, 2 replicates each.

Dataset Information

Deubiquitinase Vulnerabilities Identified through Activity Based Protein Profiling in Non-Small Cell Lung Cancer

Publications

Deubiquitinase Vulnerabilities Identified through Activity-Based Protein Profiling in Non-Small Cell Lung Cancer.

Similar Datasets

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