Inhibition of Erb-B2 Receptor Tyrosine Kinase 3 and Associated Regulatory Pathways Potently Impairs Malignant Peripheral Nerve Sheath Tumor Proliferation and Survival.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential therapeutic targets, previous studies used genome-scale shRNA screens that implicated the neuregulin-1 receptor erb-B2 receptor tyrosine kinase 3 (erbB3) in MPNST proliferation and/or survival. The current study shows that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src- and erbB3-mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, and calmodulin) and parallel (AZD1208) signaling pathways involving mitogen-activated protein kinase and mammalian target of rapamycin reduced MPNST proliferation and survival. ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied calmodulin-dependent protein kinase IIα phosphorylation site in an Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and TFP-induced erbB3 and calmodulin-dependent protein kinase IIα phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events; and when combined with TFP, it even more effectively reduces proliferation and survival compared with monotherapy. These findings implicate erbB3, calmodulin, proviral integration site of Moloney murine leukemia kinases, and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.

Mechanisms of Receptor Tyrosine-Protein Kinase ErbB-3 (ERBB3) Action in Human Neoplasia.

It is well established that the epidermal growth factor (EGF) receptor, receptor tyrosine-protein kinase erbB-2 (ERBB2)/human EGF receptor 2 (HER2), and, to a lesser extent, ERBB4/HER4, promote the pathogenesis of many types of human cancers. In contrast, the role that ERBB3/HER3, the fourth member of the ERBB family of receptor tyrosine kinases, plays in these diseases is poorly understood and, until recently, underappreciated. In large part, this was because early structural and functional studies suggested that ERBB3 had little, if any, intrinsic tyrosine kinase activity and, thus, was unlikely to be an important therapeutic target. Since then, however, numerous publications have demonstrated an important role for ERBB3 in carcinogenesis, metastasis, and acquired drug resistance. Furthermore, somatic ERBB3 mutations are frequently encountered in many types of human cancers. Dysregulation of ERBB3 trafficking as well as cooperation with other receptor tyrosine kinases further enhance ERBB3's role in tumorigenesis and drug resistance. As a result of these advances in our understanding of the structure and biochemistry of ERBB3, and a growing focus on the development of precision and combinatorial therapeutic regimens, ERBB3 is increasingly considered to be an important therapeutic target in human cancers. In this review, we discuss the unique structural and functional features of ERBB3 and how this information is being used to develop effective new therapeutic agents that target ERBB3 in human cancers.

Recent Advances in the Diagnosis and Pathogenesis of Neurofibromatosis Type 1 (NF1)-associated Peripheral Nervous System Neoplasms.

The diagnosis of a neurofibroma or a malignant peripheral nerve sheath tumor (MPNST) often raises the question of whether the patient has the genetic disorder neurofibromatosis type 1 (NF1) as well as how this will impact the patient's outcome, what their risk is for developing additional neoplasms and whether treatment options differ for NF1-associated and sporadic peripheral nerve sheath tumors. Establishing a diagnosis of NF1 is challenging as this disorder has numerous neoplastic and non-neoplastic manifestations which are variably present in individual patients. Further, other genetic diseases affecting the Ras signaling cascade (RASopathies) mimic many of the clinical features of NF1. Here, we review the clinical manifestations of NF1 and compare and contrast them with those of the RASopathies. We also consider current approaches to genetic testing for germline NF1 mutations. We then focus on NF1-associated neurofibromas, considering first the complicated clinical behavior and pathology of these neoplasms and then discussing our current understanding of the genomic abnormalities that drive their pathogenesis, including the mutations encountered in atypical neurofibromas. As several neurofibroma subtypes are capable of undergoing malignant transformation to become MPNSTs, we compare and contrast patient outcomes in sporadic, NF1-associated and radiation-induced MPNSTs, and review the challenging pathology of these lesions. The mutations involved in neurofibroma-MPNST progression, including the recent identification of mutations affecting epigenetic regulators, are then considered. Finally, we explore how our current understanding of neurofibroma and MPNST pathogenesis is informing the design of new therapies for these neoplasms.