Abstract
BackgroundRecently we identified a relationship between human cytomegalovirus (hCMV) and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR → ERK pathway. Our previously characterized, novel mouse organ culture model of mouse CMV (mCMV)-induced tumorigenesis displays a number of histologic and molecular characteristics similar to human MEC.MethodsNewborn mouse submandibular glands (SMGs) were incubated with 1 × 105 PFU/ml of lacZ-tagged mCMV RM427+ on day 0 for 24 hours and then cultured in virus-free media for a total of 6 or 12 days with or without EGFR/ERK inhibitors and/or aciclovir. SMGs were collected for histology, immunolocalization (pERK, FN, IL-6), viral distribution, or Western blot analysis (pERK).ResultsHere we report: (1) mouse SMG tumors soon exhibit an acquired resistance to EGFR/ERK pathway kinase inhibitors, alone or in combination; (2) long term tumor regression can only be sustained by concurrent inhibitor and antiviral treatment; (3) CMV-dependent, kinase inhibitor resistance is associated with overexpression of fibronectin and IL-6 proteins in abnormal stromal cells.ConclusionsAcquired resistance to kinase inhibitors is dependent upon CMV dysregulation of alternative pathways with downstream effectors common with the targeted pathway, a phenomenon with important therapeutic implications for human MEC of salivary glands.
Highlights
We identified a relationship between human cytomegalovirus and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR → ERK pathway
Newborn (NB) mouse Submandibular glands (SMG) organs were cultured with 1 × 105 plaque-forming units (PFU)/ml mouse CMV (mCMV) for 24 h and maintained for 6 or 12 days; controls consisted of NB SMG organs cultured for identical periods in control medium
NB SMGs are infected with 1 × 105 PFU/ml mCMV for 24 hr in the presence of either 10 μM GEF or 10 μM U0126 and cultured to day 12 in control medium with the respective inhibitor along with the addition of either 10 μM U1026 (GEF + Addition on U0126 beginning on day 6 (D6U)) or 10 μM GEF beginning on day 6 (U + Addition of gefitinib beginning on day 6 (D6GEF))
Summary
We identified a relationship between human cytomegalovirus (hCMV) and human salivary gland (SG) mucoepidermoid carcinoma (MEC) in over 90% of cases; tumorigenesis in these cases uniformly correlated with active hCMV protein expression and an upregulation of the EGFR → ERK pathway. We report that EGFR/ERK pathway inhibition initially attenuates tumor progression and induces tumor regression, it is uniformly limited by an acquired drug resistance, and subsequent failure to sustain either tumor regression or stability. This drug resistance appears to be dependent upon CMV dysregulation of alternative pathways with downstream effectors common with the targeted pathway. These observations likely have important therapeutic implications for human salivary gland tumors
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