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RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [PDX]

ABSTRACT: RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [PDX]

PROVIDER: PRJNA1228518 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32490481_1.fastq.gz	Fastqsanger.gz
	SRR32490481_2.fastq.gz	Fastqsanger.gz
	SRR32490482_1.fastq.gz	Fastqsanger.gz
	SRR32490482_2.fastq.gz	Fastqsanger.gz
	SRR32490483_1.fastq.gz	Fastqsanger.gz

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RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [PDX]

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

RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [H2110]

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RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [H2110]

Project description:RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [H2110]

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Mutant RIT1 cooperates with YAP to drive an EMT-like lung cancer state

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.

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Transcriptomic profiling identifies unique and shared functions of oncogenic KRAS and RIT1

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.

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Affinity purification MS of human Ubiquitin-tagged RIT1

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Project description:To investigate the impact of mutant RIT1 expression in cardiac cells, we isolated neonatal cardiomyocytes from mice harbouring an engineered Rit1 locus with Cre recombinase-inducible expression of the pathogenic variant Rit1M90I. Upon isolation, cardiomyocytes were treated with adenoviruses encoding for Cre recombinase to induce expression of the Rit1M90I variant.

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Project description:In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here we explored the role of exportin 1 in NE transformation. We observed upregulated exportin 1 in lung and prostate pre-transformation adenocarcinomas. Exportin 1 was induced upregulated following genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation and extended response to targeted therapies in both lung anddifferent TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the AR inhibitor enzalutamide, and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE transformationNE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs tumors after NE transformation to standard cytotoxics. Together these data nominate exportin 1 inhibition as a novel potential therapeutic approach target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.

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Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 downregulation in lung and prostate cancers [ATAC-seq]

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Transcriptomic profiling of oncogenic RIT1 and activated YAP1 in lung epithelial cells

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