OUR RESEARCH
RHO and RAS GTPases are molecular switches
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RAS GTPases (e.g., KRAS) and the highly similar RHO (RAS homologous) GTPases (e.g., RHOA) are key signaling proteins that regulate a wide variety of different cellular functions and, when dysregulated, drive pathological processes including cancer as well as developmental and neurological disorders. RAS and RHO proteins function as extracellular-signal-regulated molecular switches that cycle between an inactive GDP-nucleotide-bound state and an active GTP-nucleotide-bound form. Their GTPase cycle is stimulated by RAS- and RHO-specific GEFs (Guanine Nucleotide Exchange Factors) and GAPs (GTPase Activating Proteins).
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The GTPase cycle of RAS and RHO GTPases
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The unique features of RHO GTPases in cancer
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Cancer-associated mutations in the RAS GTPases KRAS, HRAS and NRAS were identified 40 years ago, with activating mutational hotspots at the residues G12, G13 and Q61. K/H/NRAS are now established cancer drivers and RAS GTPases are one of the most frequently mutated oncogene family in cancer. Only 10 years ago, mutations in RHO GTPases like RHOA and in fusion genes of RHOA-regulating RhoGAPs were discovered in multiple cancer types. Surprisingly, the genetic mechanisms such as the location of the mutational hotspots between RAS and RHO proteins are strikingly different. Despite conversation of the RAS mutational hotspots in RHOA and other RHO GTPases, cancer-associated alterations in RHOA are found at R5, G17, Y42 and L57. Thus, extrapolations from RAS are of limited value and it is unknown whether these RHOA mutations act as oncogenes or tumor suppressors and how they drive tumorigenesis. Consequently, RHOA-dependent cancers such as gastric adenocarcinoma as well as certain hematopoietic and lymphoid cancers including T- and B-cell lymphomas are highly lethal due to the lack of effective therapies.
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Cancer-associated mutational hotspots in KRAS and RHOA
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How does aberrant RHOA function drive gastric cancer growth and therapy resistance?
We use diffuse gastric cancer as a model to advance our limited understanding of RHOA function in tumorigenesis. Gastric cancer is the 4th leading cause of cancer deaths worldwide. It is divided into two histologic types: intestinal and diffuse. Diffuse gastric cancer is with a 5-year survival of less than 10% the most aggressive and highly lethal variant. A significant increase of cases among younger people (30-40s) has been observed in the recent years. Until today, there are no approved diffuse gastric cancer-targeted therapies available. The recent finding that 42% of diffuse gastric cancer patients harbor genetic alterations associated with dysregulated RHOA function, induced either by missense RHOA mutations or fusion genes of RHOA-regulating RhoGAPs, represents a promising opportunity to develop new, precision-medicine-based therapies for this deadly cancer. Recent studies also indicate that aberrant RHOA function plays a critical, yet poorly understood role even in KRAS-driven intestinal gastric cancer, specifically in therapy resistance.
We study RHOA's canonical functions as key regulator of actin-cytoskeletal dependent processes such as metastasis and cell plasticity, but also RHOA's non-canonical roles in cancer. Our research addresses the following questions, with the goal of discovering new treatment strategies:
We study RHOA's canonical functions as key regulator of actin-cytoskeletal dependent processes such as metastasis and cell plasticity, but also RHOA's non-canonical roles in cancer. Our research addresses the following questions, with the goal of discovering new treatment strategies:
- What are the molecular mechanisms by which RHOA mutations and RhoGAP fusion genes drive diffuse gastric cancer growth and how can we therapeutically target these mechanisms?
- What are the RHOA-induced mechanisms that drive therapy resistance in KRAS-dependent intestinal gastric cancer? How can we overcome these mechanisms in order to define effective combination therapies?
How do RHO GTPases modulate therapy resistance in KRAS-driven pancreatic cancer?
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Pancreatic cancer is one of the top 3 causes of cancer deaths in the US, with a 5-year survival rate of only 13%. The KRAS oncogene is mutationally activated in ~95% of pancreatic ductal adenocarcinoma. Monotherapy targeting KRAS function leads eventually to therapy-induced resistance in most patients. The challenge is to identify these resistance mechanisms in order to develop combination therapies that achieve long-term durable responses. We found that directly and indirectly targeting KRAS function using a variety of different FDA-approved and preclinical inhibitors is associated with dysregulated RHO GTPase functions (e.g., cell plasticity) in pancreatic cancer and other RAS-driven cancers. Our research aims to elucidate the RHO GTPase-induced mechanisms that modulate therapy resistance in KRAS-driven pancreatic cancer, with the goal of defining new combination strategies.
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Patient-derived pancreatic cancer cells treated with
the vehicle DMSO (left) or an inhibitor targeting KRAS function (right). |
