Expression of RIT1 M90I in primary cardiomyocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE207188 | GEO | 2022/12/01
REPOSITORIES: GEO
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Project description:The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma, but many rare driver mutations remain untargeted. Somatic mutations of the “Ras-like in all tissues” (RIT1) gene are non-canonical driver events in lung cancer, occurring in ~2% of lung adenocarcinomas in a mutually exclusive fashion with KRAS and EGFR mutations. Patients with RIT1-mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies for RIT1-mutant lung cancer. Here we report a new mouse model with inducible regulation of the cancer-associated RIT1M90I variant. We show that autochthonous expression of RIT1M90I in the lung weakly promotes cancer alone or in combination with loss of the p53 tumor suppressor. However, potent synergy between RIT1M90I and inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1M90I-driven lung cancer in vitro and in vivo. These data identify YAP/TEAD as an important mediator of RIT1’s oncogenic potential and nominate TEAD as an important drug target in RIT1-mutant lung cancer.
2025-07-11 | GSE302412 | GEO
Project description:The discovery of oncogene addiction in cancer has led to the development of over a dozen FDA-approved biomarker-driven therapies in lung adenocarcinoma, but many rare driver mutations remain untargeted. Somatic mutations of the “Ras-like in all tissues” (RIT1) gene are non-canonical driver events in lung cancer, occurring in ~2% of lung adenocarcinomas in a mutually exclusive fashion with KRAS and EGFR mutations. Patients with RIT1-mutant lung cancer lack targeted therapy treatment options, and a lack of pre-clinical models has hindered the development of therapeutic strategies for RIT1-mutant lung cancer. Here we report a new mouse model with inducible regulation of the cancer-associated RIT1M90I variant. We show that autochthonous expression of RIT1M90I in the lung weakly promotes cancer alone or in combination with loss of the p53 tumor suppressor. However, potent synergy between RIT1M90I and inactivation of Nf2 and p53 drives an aggressive lung cancer with 100% penetrance and short latency. We show this oncogenic cooperation is driven by synergistic activation of cJUN, a component of the AP-1 complex. Therapeutic inhibition of MEK and YAP/TEAD suppressed RIT1M90I-driven lung cancer in vitro and in vivo. These data identify YAP/TEAD as an important mediator of RIT1’s oncogenic potential and nominate TEAD as an important drug target in RIT1-mutant lung cancer.
2025-07-14 | GSE302452 | GEO
Project description:Expression of RIT1 M90I in primary cardiomyocytes
| PRJNA854086 | ENA
Project description:To investigate whether MEK1/2 inhibition attenuates MAPK signaling in RIT1 M90I mice and ameliorates cardiac tissue overgrowth, we treated a cohort of 4-week-old mice harboring a germline Rit1M90I variant with the allosteric MEK1/2 inhibitor trametinib (MEKi).
2022-12-01 | GSE207187 | GEO
Project description:Human RIT1 was tagged with HA tag + N or C terminal ubiquitin (HA-Ubiqutin-RIT1 and HA-RIT1-Ubiqutin) and compared with empty vector (EV) or S35N/M90I RIT1 mutant (HA-RIT1 S35N/M90I). The constructs were expressed in human 293T cells and affinity purified using HA beads. RIT1 interacting proteins were compared by quantifying MS1 extracted chromatograms of peptides identified in conventional target-decoy database search.
2024-07-09 | PXD047228 | Pride
Project description:Based on xenograft data, we have found that YAP1 activation synergizes with RIT1M90I to promote lung cancer. To investigate the molecular basis for the observed functional synergy, we performed whole-genome RNA-seq in SALE cells expressing RIT1M90I and YAP15SA individually or in combination. We find that RIT1M90I and YAP15SA induced very different transcriptional states with little correlation. And, that transcripts altered by RIT1M90I were not enriched for a YAP1 gene signature, whereas YAP15SA drove activation of this signature. In addition, we find that when RIT1M90I and YAP15SA w co-expressed, YAP1-regulated gene expression was enhanced by RIT1M90I compared to YAP15SA alone, with known YAP1 targets such as TNNT2, ITGB2, and COL4A3 showing 2.5-3.6 fold increased expression compared to YAP15SA alone. These data suggest that RIT1M90I on its own does not trigger YAP1 target transcription but may instead enhance activation of YAP1 targets in settings of YAP1 activation, such as tumors with Hippo pathway loss.
2021-05-31 | GSE165631 | GEO
Project description:RIT1 is a small GTPase of the RAS family and RIT1 mutations have been identified in lung cancer, leukemias, and the developmental disorder Noonan syndrome. Mutations in RIT1 lead to increased levels of this oncoprotein due to impaired proteolysis, resulting in dysregulation of RAS/MAPK and other pathways. Here we document the diversity of RIT1 mutations in human lung cancer and show that physiologic expression of RIT1 M90I is sufficient to drive autochthonous lung tumor development in vivo in mouse models. Due to the current lack of targeted therapies for this oncoprotein, we undertake different and complementary methods to either inhibit RIT1 directly or the downstream RAS/MAPK pathway. Through a proof-of-concept chemical biology approach, we discover that RAS tri-complex inhibitors bind directly to GTP-bound RIT1 and lead to tumor shrinkage. These molecules provide a feasible therapeutic approach for RIT1-driven lung tumors.
2025-05-08 | GSE290502 | GEO
Project description:RIT1 is a small GTPase of the RAS family and RIT1 mutations have been identified in lung cancer, leukemias, and the developmental disorder Noonan syndrome. Mutations in RIT1 lead to increased levels of this oncoprotein due to impaired proteolysis, resulting in dysregulation of RAS/MAPK and other pathways. Here we document the diversity of RIT1 mutations in human lung cancer and show that physiologic expression of RIT1 M90I is sufficient to drive autochthonous lung tumor development in vivo in mouse models. Due to the current lack of targeted therapies for this oncoprotein, we undertake different and complementary methods to either inhibit RIT1 directly or the downstream RAS/MAPK pathway. Through a proof-of-concept chemical biology approach, we discover that RAS tri-complex inhibitors bind directly to GTP-bound RIT1 and lead to tumor shrinkage. These molecules provide a feasible therapeutic approach for RIT1-driven lung tumors.
2025-05-08 | GSE290503 | GEO
Project description:Aberrant activation of RAS oncogenes is a prevalent event in lung adenocarcinoma, with somatic mutation of KRAS occurring in ~30% of tumors. Recently, we identified somatic mutation of the RAS-family GTPase RIT1 in lung adenocarcinoma, but relatively little is known about the biological pathways regulated by RIT1 and how these relate to the oncogenic KRAS network. Here we present (quantitative proteomic and) transcriptomic profiles from KRAS-mutant and RIT1-mutant isogenic lung epithelial cells and globally characterize the signaling networks regulated by each oncogene.
2020-03-06 | GSE146479 | GEO
Project description:These data accompany our publication "RIT1 oncoproteins escape LZTR1-mediated proteolysis" (Castel P., et al. Science, 2019).
Experiment 1:
Identification of LZTR1 as an interacting partner of RIT1
Q Exactive Plus
P20161208-02 FLAG GFP
P20161208-03 FLAG RIT1
LTQ Orbitrap Velos
V20170407-01 GST empty vector
V20170407-03 GST RIT1
V20170407-06 HA empty vector
V20170407-07 HA RIT1
Experiment 2:
Identification of K135 and K187 ubiquitination sites in RIT1
Q Exactive Plus
P20180408-01 FLAG-RIT1 / empty vector / empty vector (replicate 1)
P20180408-02 FLAG-RIT1 / LZTR1 / empty vector (replicate 1)
P20180408-03 FLAG-RIT1 / empty vector / TUBE (replicate 1)
P20180408-04 FLAG-RIT1 / LZTR1 / TUBE (replicate 1)
P20180408-06 GST-RIT1 / empty vector / empty vector (replicate 1)
P20180408-07 GST-RIT1 / LZTR1 / empty vector (replicate 1)
P20180408-08 GST-RIT1 / empty vector / TUBE (replicate 1)
P20180408-09 GST-RIT1 / LZTR1 / TUBE (replicate 1)
P20180408-11 GST-RIT1 / empty vector / empty vector (replicate 2)
P20180408-12 GST-RIT1 / LZTR1 / empty vector (replicate 2)
P20180408-13 GST-RIT1 / empty vector / TUBE (replicate 2)
P20180408-14 GST-RIT1 / LZTR1 / TUBE (replicate 2)
P20180408-16 FLAG-RIT1 / empty vector / empty vector (replicate 2)
P20180408-17 FLAG-RIT1 / LZTR1 / empty vector (replicate 2)
P20180408-18 FLAG-RIT1 / empty vector / TUBE (replicate 2)
P20180408-32 FLAG-RIT1 / LZTR1 / TUBE (replicate 2)
2019-02-14 | MSV000083444 | MassIVE