Gastrointestinal stromal tumors (GISTs) are the most common sarcomas in humans, and generally result from constitutively activating mutations in the KIT or PDGFRA receptor tyrosine kinases as the initiating oncogenetic events.1,2 For this reason, most metastatic GISTs respond dramatically to therapies with KIT/PDGFRA inhibitors, such as imatinib, sunitinib and regorafenib.1,2 Asymptomatic and mitotically-inactive KIT/PDGFRA-mutant “microGISTs” are found in one third of adults, but most of these small tumors never progress to malignancy, underscoring that a progression of oncogenic mutations is required, before early innocuous GISTs transform into lethal metastasizing cancers. Mutations causing cell cycle dysregulation are one of the key events driving GIST oncogenic progression, and this is reflected in the clinically useful classification of GISTs into “low-risk” vs. “high-risk” categories, which are GISTs, respectively, with low vs. high risk of metastatic recurrence after surgical removal of the primary tumor. Mitotic activity is one crucial indicator of “risk,” underscoring the crucial role of cell cycle dysregulation mutations in progression of early GIST to a disease stage which can acquire metastatic ability. Biallelic inactivation of the CDKN2A/p16 tumor suppressor often enables GIST progression to the high-risk stage, as supported by associations between p16 loss and aggressive clinical behavior in GIST.3 Likewise, MDM2 or TP53 mutations, resulting in TP53 inactivation, are found in a subset of advanced GISTs.4 These cell cycle dysregulation mutations contribute substantially to GIST genetic progression, and are likely necessary for transition from low-risk to high-risk GIST. In a recent publication, we reported the discovery of highly recurrent DMD mutations, inactivating the dystrophin protein and thereby conferring metastatic potential, as late events in GIST progression.5 Dystrophin inactivation is responsible for the most common types of muscular dystrophy, and dystrophin-related biology and therapeutics have been studied intensively in the dystrophies. Genomic mechanisms of dystrophin inactivation were identified in 96 percent of metastatic GISTs, whereas dystrophin inactivation was not found in low-risk GISTs. The dystrophin 427kDa myogenic isoform was expressed robustly in interstitial cells of Cajal, which are the nonneoplastic cell counterpart to GIST, as well as in low-risk GISTs. Previous studies also suggested that dystrophin inactivation predisposes to development of myogenic cancers: as one example, rhabdomyosarcomas occur at increased frequency in mice with dystrophin deficiency. Our study advances these concepts by providing evidence that dystrophin has ubiquitous tumor suppressor roles in certain human cancers with myogenic features, particularly in GIST, rhabdomyosarcoma and leiomyosarcoma. Notably, dystrophin inactivation in GISTs was the last identifiable genomic event during tumor progression, arising within subclones of high-risk GISTs and present in all metastases arising from those GISTs. These findings jibe well with functional studies in dystrophin deficient GIST lines, where dystrophin restoration inhibited cell migration, invasion, anchorage independence, and invadopodia formation.5 In turn, the findings fit with the known biology of dystrophin, as a structural link between the actin-based cytoskeleton and extracellular matrix. Together, these observations establish a model of oncogenic progression in GIST, in which KIT/PDGFRA oncogenic mutations are the initiating events, creating a clonal albeit minimally proliferative benign pre-cancer, after which mutations of cell cycle regulators cause transition from low-risk to high-risk GIST, and – finally – dystrophin inactivation enables metastatic spread. Based on this new model for myogenic cancer progression, one can envision effective combination therapeutic strategies, targeting cell cycle and dystrophin defects. Demonstration of dystrophin inactivating mutations in GIST and other myogenic cancers has therapeutic relevance, because targeted therapies are already under development for muscular dystrophies, with the aim of restoring dystrophin function. These therapeutic approaches in muscular dystrophies provide a ready departure point for engaging similar strategies in dystrophin-deficient cancers. Dystrophin functional restoration can be accomplished by various approaches, including viral delivery of a functional DMD gene, exon skipping to restore the DMD reading frame, read-through of translation stop codons, and increased expression of the compensatory utrophin gene. Each of these strategies is undergoing preclinical and/or clinical evaluation as a potential therapy for Duchenne muscular dystrophy.6,7 These approaches warrant evaluation as potential therapeutic agents in oncology, particularly in myogenic cancers in which tumorigenic progression is fostered by dystrophin inactivation.
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Open Access
Dec 1, 2015
K Jasek + 4
