Human Genetic Relevance and Potent Antitumor Activity of Heat Shock Protein 90 Inhibition in Canine Lung Adenocarcinoma Cell Lines

Clemente-Vicario, Francisco; Álvarez, Carlos E.; Rowell, Jennie L.; Roy, Satavisha; London, Cheryl A.; Kisseberth, William C.; Lorch, Gwendolen

doi:10.1371/journal.pone.0142007

Cited by 13 publications

(9 citation statements)

References 64 publications

(85 reference statements)

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“…IHC was performed using antibodies against pAkt Ser473 (phosphorylated Akt in Ser473, rabbit monoclonal antibody, diluted 1:50; Cell Signaling Technologies, Danvers, Massachusetts), pS6 Ser235/236 (phosphorylated S6 in Ser235/236, rabbit antibody, diluted 1:200; Cell Signaling Technologies, Danvers, Massachusetts) and Ki‐67 (mouse monoclonal anti‐human antibody, diluted 1:100; Dako, Carpinteria, California). All selected antibodies have been previously validated in dog tissues . Negative assay control included TMA slides processed for IHC on which the primary antibody was substituted for an isotype‐specific immunoglobulin (according to the primary antibody used: Rabbit (DA1E) mAb IgG XP Isotype Control; Cell Signaling Technologies or Mouse (G3A1) mAb IgG1 Isotype Control; Cell Signaling Technologies).…”

Section: Methodssupporting

confidence: 92%

Dysregulated expression of the key effectors of the mammalian target of rapamycin signalling pathway in cutaneous papillomas of dogs

Ressel

Massone

Barbeito

2019

Vet Comparative Oncology

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Cutaneous papillomas (CP) are one of the most common skin neoplasms in dogs. Different murine models have shown that persistent activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway has a central role in the development and progression of CP. The purpose of this study were to evaluate the immunohistochemical expression pattern of two key molecules involved in the PI3K/Akt/mTOR signalling pathway, pAkt Ser473 , and pS6 Ser235/236 , on 36 canine specimens of CP using a tissue microarray. The resultsshow that the PI3K/Akt/mTOR signalling pathway is persistently activated in CP of dogs, pointing to this pathway as a potential therapeutic target.

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Section: Methodssupporting

confidence: 92%

Dysregulated expression of the key effectors of the mammalian target of rapamycin signalling pathway in cutaneous papillomas of dogs

Ressel

Massone

Barbeito

2019

Vet Comparative Oncology

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“…None of these cell lines bore additional mutations in HER2. We have previously shown that BACA and CLAC do not contain HER2 amplification (by array comparative genomic hybridization) [34]. We next assessed HER2 activation in one HER2 V659E cPAC cell lines and three HER2 WT cell lines (two cPAC, papillary and unknown subtypes, and one cPASC) by…”

Section: Her2 Expression In Primary Canine Lung Cancermentioning

confidence: 99%

Identification of frequent activating HER2 mutations in primary canine pulmonary adenocarcinoma

Lorch

Sivaprakasam

Zismann

et al. 2019

Preprint

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Naturally occurring primary canine lung cancers are aggressive malignancies that are increasingly common in pet dogs. They share clinicopathologic features with human lung cancers in never-smokers, but their genetic underpinnings are unknown. Through multi-platform sequencing of 90 primary canine lung tumors or cell lines, we discovered somatic, coding HER2 (ERRB2) point mutations in 37% of canine pulmonary adenocarcinomas (cPAC, 28/76), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. In cPASC, KRAS, and TP53 were the most frequently mutated genes (18% each). In cPSCC, no recurrently mutated genes were identified, but individual somatic coding mutations were found in BRAF and PTPN11. In cPAC, we also identified recurrent somatic mutation of TP53 (12%), SMAD4(5.3%), PTEN (5.3%), and VHL (4.0%). cPACs assessed by exome sequencing displayed a low mutation burden (median 64 SNVs, 19 CNVs and 1 SV). The majority (93%) of HER2 mutations are hotspot V659E transmembrane domain (TMD) mutations comparable to activating mutations at this same site in human cancer. Other HER2 mutations identified in this study were located in the extracellular and TMD. The HER2 V659E mutation was detected in the plasma of 33% (2/6) of dogs with localized tumors bearing this mutation. HER2 V659E correlated with constitutive phosphorylation of Akt in cPAC cell lines and HER2 V659E lines displayed hypersensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2 wild-type cell lines. These findings have immediate translational and comparative relevance for lung cancer and HER2 inhibition.

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“…Canine/human comparative oncology—the study of analogous cancers in both humans and dogs—is playing increasingly important roles in advancing research in a variety of cancers, from both the basic science and clinical perspectives . Interspecies cancer studies have led to new insights into breast cancer, osteosarcoma, lung cancer and bladder cancer . Invasive bladder cancer in particular has become established as a model for comparative oncology due to the respective canine and human malignancies' similarities in environmental risk factors, tumor histology, tumor ploidy, sites of metastases, driver mutations, and modes of treatment .…”

Section: Introductionmentioning

confidence: 99%

Cross‐species analysis of the canine and human bladder cancer transcriptome and exome

Ramsey

Goodall

et al. 2017

Genes Chromosomes & Cancer

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We investigated the correspondence between transcriptome and exome alterations in canine bladder cancer and the correspondence between these alterations and cancer-driving genes and transcriptional alterations in human bladder cancer. We profiled canine bladder tumors using mRNA-seq and exome-seq in order to investigate the similarity of transcriptional alterations in bladder cancer, in humans and canines, at the levels of gene functions, pathways, and cytogenetic regions. We found that the transcriptomes of canine and human bladder cancer are remarkably similar at the functional and pathway levels. We demonstrated that canine bladder cancer involves coordinated differential expression of genes within cytogenetic bands, and that these patterns are consistent with those seen in human bladder cancer. We found that genes that are mutated in canine bladder cancer are more likely to be transcriptionally downregulated than non-mutated genes, in the tumor. Finally we report three novel mutations (FAM133B, RAB3GAP2, and ANKRD52) for canine bladder cancer.

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Human Genetic Relevance and Potent Antitumor Activity of Heat Shock Protein 90 Inhibition in Canine Lung Adenocarcinoma Cell Lines

Cited by 13 publications

References 64 publications

Dysregulated expression of the key effectors of the mammalian target of rapamycin signalling pathway in cutaneous papillomas of dogs

Dysregulated expression of the key effectors of the mammalian target of rapamycin signalling pathway in cutaneous papillomas of dogs

Identification of frequent activating HER2 mutations in primary canine pulmonary adenocarcinoma

Cross‐species analysis of the canine and human bladder cancer transcriptome and exome

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