Data Availability StatementAll relevant data are inside the paper. NEU3 overexpression, therefore hypothesizing that NEU3 overexpressing patients might reap the benefits of EGFR targeted therapies also in lack of EGFR point mutations. Overall, the manifestation of NEU3 may be a book diagnostic marker in NSCLC because, by its capability to stimulate EGFR downstream pathways with immediate and indirect systems, it may help in the identification of patients who can profit from EGFR targeted therapies in absence of EGFR activating mutations or from new combinations of EGFR and Akt inhibitors. Introduction Lung cancer is the leading cause of cancer death in both sexes ; it is generally classified in Small Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC), the latter accounting for approximately 85C95% of all lung cancers. Among NSCLC, adenocarcinomas (AC) are the most frequent histotype, representing 40% of diagnosed patients. Current conventional treatment for lung cancer consists of surgery for operable patients, followed by chemo/radiotherapy. However, the prognosis is usually poor especially for patients with advanced disease. In this setting, the introduction of targeted therapies has led to improved outcome for AC patients; one such target is the epidermal growth factor receptor (EGFR), which is frequently overexpressed and aberrantly activated in NSCLC . When EGFR binds to several specific ligands, multiple signalling pathways are activated including the RAS/RAF/ERK/MAPK pathway, resulting in cell proliferation, and the PI3K/Akt pathway, STAT (Signal Transducers and Activators of Transcription) 3 and 5 signal transduction pathways, resulting in the evasion of apoptosis . EGFR has been exploited as a molecular target of two different kinds of molecules: monoclonal antibodies (mAbs), directed against the extracellular domain and interfering with receptor dimerization (like Cetuximab and Panitumumab) and tyrosine kinase inhibitors (TKI), blocking the intracellular receptor kinase activity . mAbs against EGFR BAPTA/AM are active when EGFR is altered through protein expression, typically occurring in colorectal (CRC) cancer, while TKIs can inhibit the EGFR protein when a mutation occurs in its tyrosine kinase, encoded by exons 18C21. The latter is the typical EGFR activation found in BAPTA/AM lung cancer patients, occurring in 10C40% of patients, more frequently in Asians, females, non-smokers, and in adenocarcinomas. Over the last decade, a variety of TKI have received Food and Drug Administration (FDA) approval for treating NSCLC, among which Gefitinib (Iressa) and Erlotinib (Tarceva) are currently in use for advanced and metastatic NSCLC in the first line of treatment [5C7]. However, not all EGFR mutations in the tyrosine kinase domain display the same effect with respect to TKI efficacy: in-frame deletions in exon 19 as well as L858R and L861Q point mutations in exon 21 are associated with the best response BAPTA/AM to TKI. Point mutations occurring in exon 18 (in codons 709 and 719) are associated with an intermediate response, while alterations in exon 20 lead to TKI resistance. One of the last mutations, the T790M change, is the typical mechanism of acquired resistance occurring in patients treated with gefitinib or erlotinib: consequently, individuals developing this type of mutation should be treated with a different type of TKI (i.e.: irreversible TKI, or second-generation TKI)[8C11]. Sialidases (EC 22.214.171.124), or neuraminidases, are distributed glycohydrolases widely, removing sialic acidity residues from a number of glycoconjugate Rabbit polyclonal to TOP2B . BAPTA/AM In human beings, four sialidases with different subcellular localizations and biochemical features have already been referred to: a lysosomal sialidase (NEU1), a cytosolic sialidase (NEU2), a plasma membrane-associated sialidase (NEU3) along with a mitochondrial/endoplasmic reticulum (ER) sialidase (NEU4) . Problems in glycosylation are recognized to are likely involved in malignancy , becoming connected with invasiveness and metastatic potential in tumor cells . Among sialidases, the plasma membrane-associated NEU3  can be mixed up in regulation of several trans-membrane signalling procedures [16,17] and it has been shown to behave not merely on gangliosides within its membrane,.