Emerging targets in sarcoma: Rising to the challenge of RAS signaling in undifferentiated pleomorphic sarcoma

Sarcomas are an intriguingly complex set of tumors, arising from mesenchymal tissue and representing approximately 1% of all adult cancers. One of the more perplexing features of soft tissue sarcomas (STS) is their heterogeneity; this fascinatingly diverse group boasts over 50 distinct subtypes, each one unique with regard to histology and clinical management. This complexity has made it difficult to advance our molecular understanding of these tumors. Patient samples are rare, and thus researchers have been forced to combine sarcomas from multiple different subtypes when conducting genomic studies. Although some sarcomas, such as gastrointestinal stromal tumors, are defined by a simple genetic event that allows for treatment with rational therapeutics, other STS with less-defined mutations are in need of a deeper molecular understanding to identify new drug targets. Of particular note is undifferentiated pleomorphic sarcoma (UPS), the most common STS diagnosed in adults. Similar to many other STS cases, the majority of patients with UPS are treated with surgical resection and radiotherapy. In the case of metastatic disease, patients with UPS receive a combination of doxorubicin and/ or ifosfamide-based therapy, which is both toxic and demonstrates only marginal efficacy. Classically, UPS is a diagnosis of exclusion, defined by a lack of specific histological or molecular features. UPS is extremely unstable at the genomic level. The few genomic analyses of UPS conducted to date have identified dysregulation of cell cycle and tumor suppressor pathways. However, to the best of my knowledge, these studies did not report any disruptions in signal transduction pathways that may provide new molecular targets for UPS. Herein lies the challenge: How do sarcoma biologists identify new molecular targets for a notoriously radiationresistant and chemotherapy-resistant group of rare tumors? Previous advances have been made through preclinical mouse models and carefully selected patient populations. In this edition of Cancer, Serrano et al add a much needed and insightful piece to this puzzle by formally addressing the role of multiple signaling pathways in UPS tumors. This recent study formally examined the roles of the RAS/MAPK and phosphoinositide 3-kinase inhibitor (PI3K)/mammalian target of rapamycin (mTOR) pathways in human UPS tumors. Activation of RAS/MAPK signaling begins with Ras phosphorylation of RAF kinases to initiate the 3-kinase cascade of RAF, MEK, and ERK. The RAS/MEK/ERK pathway plays a pivotal role in many human cancers, and mutations in multiple Ras isoforms have been found in a variety of cancers, including colorectal (42%), lung (20%), and pancreatic (71%) cancer. These mutant Ras proteins have historically been considered “undruggable,” although new initiatives are revisiting the possibility of therapeutically targeting Ras directly, particularly because early clinical trials for RAF and ERK inhibitors have reported widespread development of resistance. Another key signaling node is the PI3K/mTOR pathway. PI3K phosphorylates AKT, which in turn activates mTOR, a key effector in protein signaling through control of ribosomal proteins S6 and eukaryotic translation initiation factor 4E (eIF-4E). This pathway has shown significant activity in other sarcoma subtypes, particularly leiomyosarcoma, but has not been examined in a large group of UPS cases. Serrano et al characterized the signaling nodes of the RAS/MEK and PI3K/mTOR pathways in a cohort of patients with localized, surgically resected UPS. They examined activation of the pathways, mutations in signaling molecules, and the impact on patient outcome. Indeed, previous mouse and human studies have emphasized the importance of the Ras pathway in both sarcomagenesis and maintenance of UPS tumors. This new study provides an additional twist in