scholarly journals Identification of frequent activating HER2 mutations in primary canine pulmonary adenocarcinoma

2019 ◽  
Author(s):  
Gwendolen Lorch ◽  
Karthigayini Sivaprakasam ◽  
Victoria Zismann ◽  
Nieves Perdigones ◽  
Tania Contente-Cuomo ◽  
...  

ABSTRACTNaturally 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 88 primary canine lung tumors or cell lines, we discovered somatic, coding HER2 (ERRB2) point mutations in 38% of canine pulmonary adenocarcinomas (cPAC, 28/74), but none in adenosquamous (cPASC, 0/11) or squamous cell (cPSCC, 0/3) carcinomas. In cPASC, PTEN was the most frequently mutated gene (18%) while one case each bore likely pathogenic HRAS, KRAS, EGFR, MET, TP53, or VHL somatic mutations. 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 (13.5%), SMAD4 (5.4%), PTEN (4.1%), and VHL (2.7%). cPACs assessed by exome sequencing displayed a low somatic mutation burden (median 64 point mutations, 19 focal copy number variants, and 1 translocation). The majority (93%) of HER2 mutations were 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 domain and TMD. HER2V659E was detected in the plasma of 33% (2/6) of dogs with localized HER2V659E tumors. HER2V659E correlated with constitutive phosphorylation of AKT in cPAC cell lines and HER2V659E lines displayed hypersensitivity to the HER2 inhibitors lapatinib and neratinib relative to HER2-wild-type cell lines. These findings have translational and comparative relevance for lung cancer and HER2 inhibition.

2014 ◽  
Vol 306 (11) ◽  
pp. C1080-C1088 ◽  
Author(s):  
Irina Lubarski ◽  
Carol Asher ◽  
Haim Garty

FXYD5 (dysadherin or also called a related to ion channel, RIC) is a transmembrane auxiliary subunit of the Na+-K+-ATPase shown to increase its maximal velocity ( Vmax). FXYD5 has also been identified as a cancer-associated protein whose expression in tumor-derived cell lines impairs cytoskeletal organization and increases cell motility. Previously, we have demonstrated that the expression of FXYD5 in M1 cells derived from mouse kidney collecting duct impairs the formation of tight and adherence junctions. The current study aimed to further explore effects of FXYD5 at a single cell level. It was found that in M1, as well as three other cell lines, FXYD5 inhibits transformation of adhered single cells from the initial radial shape to a flattened, elongated shape in the first stage of monolayer formation. This is also correlated to less ordered actin cables and fewer focal points. Structure-function analysis has demonstrated that the transmembrane domain of FXYD5, and not its unique extracellular segment, mediates the inhibition of change in cell shape. This domain has been shown before to be involved in the association of FXYD5 with the Na+-K+-ATPase, which leads to the increase in Vmax. Furthermore, specific transmembrane point mutations in FXYD5 that either increase or decrease its effect on cell elongation had a corresponding effect on the coimmunoprecipitation of FXYD5 with α Na+-K+-ATPase. These findings lend support to the possibility that FXYD5 affects cell polarization through its transmembrane domain interaction with the Na+-K+-ATPase. Yet interaction of FXYD5 with other proteins cannot be excluded.


PLoS Genetics ◽  
2021 ◽  
Vol 17 (2) ◽  
pp. e1009354
Author(s):  
Andrey A. Parkhitko ◽  
Arashdeep Singh ◽  
Sharon Hsieh ◽  
Yanhui Hu ◽  
Richard Binari ◽  
...  

The RB1 tumor suppressor is recurrently mutated in a variety of cancers including retinoblastomas, small cell lung cancers, triple-negative breast cancers, prostate cancers, and osteosarcomas. Finding new synthetic lethal (SL) interactions with RB1 could lead to new approaches to treating cancers with inactivated RB1. We identified 95 SL partners of RB1 based on a Drosophila screen for genetic modifiers of the eye phenotype caused by defects in the RB1 ortholog, Rbf1. We validated 38 mammalian orthologs of Rbf1 modifiers as RB1 SL partners in human cancer cell lines with defective RB1 alleles. We further show that for many of the RB1 SL genes validated in human cancer cell lines, low activity of the SL gene in human tumors, when concurrent with low levels of RB1 was associated with improved patient survival. We investigated higher order combinatorial gene interactions by creating a novel Drosophila cancer model with co-occurring Rbf1, Pten and Ras mutations, and found that targeting RB1 SL genes in this background suppressed the dramatic tumor growth and rescued fly survival whilst having minimal effects on wild-type cells. Finally, we found that drugs targeting the identified RB1 interacting genes/pathways, such as UNC3230, PYR-41, TAK-243, isoginkgetin, madrasin, and celastrol also elicit SL in human cancer cell lines. In summary, we identified several high confidence, evolutionarily conserved, novel targets for RB1-deficient cells that may be further adapted for the treatment of human cancer.


Planta Medica ◽  
2007 ◽  
Vol 73 (09) ◽  
Author(s):  
IO Mondranondra ◽  
A Suedee ◽  
A Kijjoa ◽  
M Pinto ◽  
N Nazareth ◽  
...  

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