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 utilize diffuse gastric cancer as a model to advance our limited understanding of RHOA functions 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.
Our research identifies the molecular mechanisms by which RHOA mutations and RhoGAP fusion genes drive diffuse gastric cancer growth and defines how can we therapeutically target these mechanisms. 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 such its contribution to the immune response.
Our research identifies the molecular mechanisms by which RHOA mutations and RhoGAP fusion genes drive diffuse gastric cancer growth and defines how can we therapeutically target these mechanisms. 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 such its contribution to the immune response.
How do RHO GTPases modulate therapy resistance in KRAS-driven cancer?
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Another research direction of our lab aims to elucidate the RHO GTPase-induced mechanisms that drive therapy resistance in KRAS-driven cancers and to identify how we can overcome these mechanisms in order to define improved combination therapies. We focus on the lethal intestinal gastric cancer as well as pancreatic and colorectal cancer where KRAS is frequently mutated.
Monotherapy targeting KRAS function leads eventually to resistance in most patients. The key challenge in the field is to identify these resistance mechanisms in order to develop combination therapies that achieve long-term durable responses. Recent studies from us and other labs indicate that aberrant RHO functions plays a critical, yet poorly understood role in KRAS-driven cancers, specifically in therapy resistance. 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 in KRAS-mutant pancreatic, colon and gastric cancer. |
The actin-cytoskeletal-dependent morphology of patient-derived pancreatic cancer cells treated with vehicle DMSO (left) as control or an inhibitor targeting KRAS function (right), visualized via immunofluorescence microscopy
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