Lineage-specific intolerance to oncogenic drivers restricts histological transformation.

TitleLineage-specific intolerance to oncogenic drivers restricts histological transformation.
Publication TypeJournal Article
Year of Publication2024
AuthorsGardner EE, Earlie EM, Li K, Thomas J, Hubisz MJ, Stein BD, Zhang C, Cantley LC, Laughney AM, Varmus H
Date Published2024 Feb 09
KeywordsAdenocarcinoma of Lung, Cell Lineage, Epithelial Cells, Humans, Lung, Lung Neoplasms, Molecular Targeted Therapy, Oncogenes, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-myc, Small Cell Lung Carcinoma

Lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC) are thought to originate from different epithelial cell types in the lung. Intriguingly, LUAD can histologically transform into SCLC after treatment with targeted therapies. In this study, we designed models to follow the conversion of LUAD to SCLC and found that the barrier to histological transformation converges on tolerance to Myc, which we implicate as a lineage-specific driver of the pulmonary neuroendocrine cell. Histological transformations are frequently accompanied by activation of the Akt pathway. Manipulating this pathway permitted tolerance to Myc as an oncogenic driver, producing rare, stem-like cells that transcriptionally resemble the pulmonary basal lineage. These findings suggest that histological transformation may require the plasticity inherent to the basal stem cell, enabling tolerance to previously incompatible oncogenic driver programs.

Alternate JournalScience
PubMed ID38330136
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