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YES1 Is a Druggable Oncogenic Target in SCLC
Esther Redin1, Eva M Garrido-Martin2, Karmele Valencia3
1Program in Solid Tumors, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Oncología (CIBERONC), The Carlos III Health Institute (ISCIII), Madrid, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), Navarra, Spain; Department of Pathology, Anatomy, and Physiology, School of Medicine, University of Navarra, Pamplona, Spain.
Introduction:
SCLC is an extremely aggressive subtype of lung cancer without approved targeted therapies. Here we identified YES1 as a novel targetable oncogene driving SCLC maintenance and metastasis.
Methods:
Association between YES1 levels and prognosis was evaluated in SCLC clinical samples. In vitro functional experiments for proliferation, apoptosis, cell cycle, and cytotoxicity were performed. Genetic and pharmacologic inhibition of YES1 was evaluated in vivo in cell- and patient-derived xenografts and metastasis. YES1 levels were evaluated in mouse and patient plasma-derived exosomes.
Results:
Overexpression or gain/amplification of YES1 was identified in 31% and 26% of cases, respectively, across molecular subgroups, and was found as an independent predictor of poor prognosis. Genetic depletion of YES1 dramatically reduced cell proliferation, three-dimensional organoid formation, tumor growth, and distant metastasis, leading to extensive apoptosis and tumor regressions. Mechanistically, YES1-inhibited cells revealed alterations in the replisome and DNA repair processes, that conferred sensitivity to irradiation. Pharmacologic blockade with the novel YES1 inhibitor CH6953755 or dasatinib induced marked antitumor activity in organoid models and cell- and patient-derived xenografts. YES1 protein was detected in plasma exosomes from patients and mouse models, with levels matching those of tumors, suggesting that circulating YES1 could represent a biomarker for patient selection/monitoring.
Conclusions:
Our results provide evidence that YES1 is a new druggable oncogenic target and biomarker to advance the clinical management of a subpopulation of patients with SCLC.
Insights
YES1 is a novel oncogene driving small cell lung cancer (SCLC) growth and metastasis. Targeting YES1 with inhibitors shows promise for treating SCLC patients, with circulating YES1 acting as a potential biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Small cell lung cancer (SCLC) is an aggressive cancer with limited targeted therapy options.
- Identifying novel oncogenes is crucial for developing new SCLC treatments.
Purpose of the Study:
- To identify and characterize novel targetable oncogenes in SCLC.
- To evaluate YES1 as a therapeutic target and biomarker in SCLC.
Main Methods:
- YES1 expression and its association with prognosis in SCLC clinical samples.
- In vitro functional assays (proliferation, apoptosis, cell cycle, cytotoxicity).
- In vivo studies using xenografts and metastasis models; evaluation of YES1 in plasma exosomes.
Main Results:
- YES1 overexpression/amplification found in 31%/26% of SCLC cases, predicting poor prognosis.
- YES1 inhibition reduced proliferation, tumor growth, and metastasis, inducing apoptosis.
- YES1 blockade with CH6953755 or dasatinib showed antitumor activity.
- Circulating YES1 in plasma exosomes may serve as a biomarker.
Conclusions:
- YES1 is a druggable oncogenic target in a subset of SCLC patients.
- Targeting YES1 offers a potential new therapeutic strategy for SCLC.
- YES1 in exosomes can be a biomarker for patient selection and monitoring.
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