| Summary: | REarranged during Transfection (RET) oncogenic rearrangements can occur in 1–2% of lung adenocarcinomas. While RET-driven NSCLC models have been developed using various approaches, no model based on patient-derived induced pluripotent stem cells (iPSCs) has yet been described. Patient-derived iPSCs hold great promise for disease modeling and drug screening. However, generating iPSCs with specific oncogenic drivers, like <i>RET</i> rearrangements, presents challenges due to reprogramming efficiency and genotypic variability within tumors. To address this issue, we aimed to generate lung progenitor cells (LPCs) from patient-derived iPSCs carrying the mutation <i>RET<sup>C634Y</sup></i>, commonly associated with medullary thyroid carcinoma. Additionally, we established a <i>RET<sup>C634Y</sup></i> knock-in iPSC model to validate the effect of this oncogenic mutation during LPC differentiation. We successfully generated LPCs from <i>RET<sup>C634Y</sup></i> iPSCs using a 16-day protocol and detected an overexpression of cancer-associated markers as compared to control iPSCs. Transcriptomic analysis revealed a distinct signature of NSCLC tumor repression, suggesting a lung multilineage lung dedifferentiation, along with an upregulated signature associated with <i>RET<sup>C634Y</sup></i> mutation, potentially linked to poor NSCLC prognosis. These findings were validated using the <i>RET<sup>C634Y</sup></i> knock-in iPSC model, highlighting key cancerous targets such as <i>PROM2</i> and <i>C1QTNF6</i>, known to be associated with poor prognostic outcomes. Furthermore, the LPCs derived from <i>RET<sup>C634Y</sup></i> iPSCs exhibited a positive response to the RET inhibitor pralsetinib, evidenced by the downregulation of the cancer markers. This study provides a novel patient-derived off-the-shelf iPSC model of RET-driven NSCLC, paving the way for exploring the molecular mechanisms involved in RET-driven NSCLC to study disease progression and to uncover potential therapeutic targets.
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