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The tyrosine kinase receptor RET is altered by genetic fusions in a subset of non-small cell lung cancers (NSCLCs). To determine if we can generate organoids with lung cancer features in this context, we used two iPSC lines overexpressing oncogenic RET-M918T and RET-C634Y mutations. Lung progenitor cells (LPCs) were generated after 18 days of culture, followed by air-liquid interface cultures giving rise to alveolar structures expressing SFTPC, TTF-1, MUC1, and CK5/6 at day +38. Transplantation of LPCs into NOD/SCID mice generated tumors harboring bronchial structures, ciliated cells, goblet cells, and the squamous cell carcinoma marker p40. Single-cell RNA sequencing analyses allowed us to determine the major genes involved with response or resistance to Selpercatinib, a major inhibitor targeting RET-altered lung cancers. These findings show that the iPSC-derived preclinical model can recapitulate some features of NSCLC and has significant potential for identifying new therapeutic targets in RET-inhibitor-refractory lung cancers.
Hwang et al. (Mon,) studied this question.