The Ras pathway is one of the most commonly deregulated pathways in cancer. Mutations in RAS genes, upstream regulators, or downstream effectors occur in the majority of human tumors. One important Ras regulatory gene involved in cancer is the NF1 tumor suppressor, which encodes a Ras GTPase-activating protein (RasGAP). NF1 catalyzes the hydrolysis of Ras-GTP to Ras-GDP and normally terminates Ras signaling. Accordingly, loss-of-function mutations in NF1 result in hyperactivated Ras. NF1 mutations underlie a common familial cancer syndrome neurofibromatosis type I (NF1). More recently, NF1 has been shown to play a role in a variety of sporadic tumors including melanoma, glioblastoma, and lung cancer. However, while the gene was cloned in 1990, surprisingly little is known about how the NF1 protein is normally regulated or functions. In addition, there are no effective therapies for NF1-mutant tumors. In this application we aim to tackle both of these important problems. Specifically, we will 1) determine how the NF1 protein is normally regulated and terminates Ras signaling, 2) deconstruct downstream and converging signaling pathways, and 3) identify broad signaling networks that are deregulated in NF1-mutant tumors. Collectively, these studies should not only reveal novel insight into NF1 and Ras signaling, but will identify key regulators and effectors in NF1-mutant tumors that may ultimately serve as therapeutic targets.
The NF1 tumor suppressor is a Ras regulator that is mutated in a familial cancer syndrome and in a variety of sporadic cancers; however, little is known about how the NF1 protein is normally regulated or functions. Moreover, there are currently no effective therapies for NF1-mutant cancers. The goal of this project is to address both of these questions by identifying upstream regulators, downstream effectors, and converging signaling pathways. These efforts will reveal novel insight into NF1 and Ras signaling, and should also identify potential therapeutic targets in NF1-mutant cancers.
| Liao, Sida; Maertens, Ophélia; Cichowski, Karen et al. (2018) Genetic modifiers of the BRD4-NUT dependency of NUT midline carcinoma uncovers a synergism between BETis and CDK4/6is. Genes Dev 32:1188-1200 |
| Malone, Clare F; Emerson, Chloe; Ingraham, Rachel et al. (2017) mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors. Cancer Discov 7:1450-1463 |
| Maertens, Ophélia; McCurrach, Mila E; Braun, Benjamin S et al. (2017) A Collaborative Model for Accelerating the Discovery and Translation of Cancer Therapies. Cancer Res 77:5706-5711 |
| Lock, Rebecca; Ingraham, Rachel; Maertens, Ophélia et al. (2016) Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers. J Clin Invest 126:2181-90 |
| Malone, Clare F; Fromm, Jody A; Maertens, Ophélia et al. (2014) Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers. Cancer Discov 4:1062-73 |
| Hollstein, Pablo E; Cichowski, Karen (2013) Identifying the Ubiquitin Ligase complex that regulates the NF1 tumor suppressor and Ras. Cancer Discov 3:880-93 |
| McLaughlin, Sara Koenig; Olsen, Sarah Naomi; Dake, Benjamin et al. (2013) The RasGAP gene, RASAL2, is a tumor and metastasis suppressor. Cancer Cell 24:365-78 |
| Maertens, Ophélia; Johnson, Bryan; Hollstein, Pablo et al. (2013) Elucidating distinct roles for NF1 in melanomagenesis. Cancer Discov 3:338-49 |
| McGillicuddy, Lauren T; Fromm, Jody A; Hollstein, Pablo E et al. (2009) Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16:44-54 |
| Johannessen, Cory M; Johnson, Bryan W; Williams, Sybil M Genther et al. (2008) TORC1 is essential for NF1-associated malignancies. Curr Biol 18:56-62 |
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