ABSTRACT
Mammalian target of rapamycin (mTOR) inhibitors are clinically effective at treating some complex lymphatic malformations (LM). The mTOR inhibitor rapamycin blocks the phosphoinositide 3-kinase (PI3K) pathway, which is commonly mutated in this condition. Although rapamycin is effective at controlling symptoms of LM, treatment courses are long, not all LMs respond to treatment, and many patients relapse after treatment has stopped. Concurrent rat sarcoma virus (RAS) pathway abnormalities have been identified in LM, which may limit the effectiveness of rapamycin. Protein tyrosine phosphatase-2 (SHP2) controls the RAS pathway upstream, and SHP2 inhibitors are being investigated for treatment of various tumors. The objective of this study was to determine the impact of SHP2 inhibition in combination with rapamycin on LM growth in vitro. Using primary patient cells isolated from a surgically resected LM, we found that combination treatment with rapamycin and the SHP2 inhibitor SHP099 caused a synergistic reduction in cell growth, migration and lymphangiogenesis. These results suggest that combination treatment targeting the PI3K and RAS signaling pathways may result in effective treatment of LMs of the head and neck.
Subject(s)
Endothelial Cells , Phosphatidylinositol 3-Kinases , Phosphatidylinositol 3-Kinases/pharmacology , Signal Transduction , Sirolimus/pharmacology , TOR Serine-Threonine KinasesABSTRACT
An infant initially diagnosed with a parotid hemangioma presented with stridor and thrombocytopenia. Diagnosis of Kaposiform hemangioendothelioma was confirmed with biopsy. The child succumbed to multi-system organ failure related to consumptive coagulopathy despite aggressive medical management. Kaposiform hemangioendothelioma is a rare head and neck tumor that may be mistaken for a hemangioma on preliminary diagnosis, which may lead to increased morbidity and mortality especially in the setting of Kasabach-Merritt phenomenon. A platelet count may provide an early and important clue to the possibility of coagulopathy; prompting physicians to look for a diagnosis other than a simple hemangioma.
Subject(s)
Laryngeal Neoplasms/diagnosis , Multiple Organ Failure/diagnosis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Disease Progression , Disseminated Intravascular Coagulation/diagnosis , Disseminated Intravascular Coagulation/therapy , Fatal Outcome , Female , Hemangioendothelioma/diagnosis , Hemangioendothelioma/therapy , Hemangioma, Capillary/diagnosis , Hemangioma, Capillary/therapy , Hemangioma, Cavernous/diagnosis , Hemangioma, Cavernous/therapy , Humans , Infant, Newborn , Kasabach-Merritt Syndrome , Laryngeal Neoplasms/therapy , Laryngoscopy/methods , Magnetic Resonance Imaging/methods , Multiple Organ Failure/etiology , Risk Assessment , Sarcoma, Kaposi/diagnosis , Sarcoma, Kaposi/therapy , Severity of Illness Index , Skin Neoplasms/diagnosis , Skin Neoplasms/therapy , Thrombocytopenia/diagnosis , Thrombocytopenia/therapy , Tracheostomy/methods , Vascular Neoplasms/diagnosis , Vascular Neoplasms/therapyABSTRACT
DNA replication stress activates a response pathway that stabilizes stalled forks and promotes the completion of replication. The budding yeast Mec1 sensor kinase, Mrc1 mediator, and Rad53 effector kinase are central to this signal transduction cascade in S phase. We report that Mec1-dependent, Rad53-independent phosphorylation of Mrc1 is required to establish a positive feedback loop that stabilizes Mec1 and the replisome at stalled forks. A structure-function analysis of Mrc1 also uncovered a central region required for proper mediator function and association with replisome components. Together these results reveal new insight into how Mrc1 facilitates checkpoint signal amplification at stalled replication forks.