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Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation

ABSTRACT: Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation

PROVIDER: PRJNA1328772 | ENA |

REPOSITORIES: ENA

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Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation

Project description:To investigate the molecular mechanisms of neuroendocrine (NE) transformation, adenocarcinomas (LUAD) to small cell lung cancer (SCLC), in lung cancer.

2025-09-15 | GSE308124 | GEO

Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation.

Project description:Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre/posttransformation samples, supports that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm. We observed enhanced expression of genes involved in the PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacologic inhibition of the PI3K/AKT pathway delayed tumor growth and NE transformation in an EGFR-mutant patient-derived xenograft model. Our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.SignificanceThe difficulty in collection of transformation samples has precluded the performance of molecular analyses, and thus little is known about the lineage plasticity mechanisms leading to LUAD-to-SCLC transformation. Here, we describe biological pathways dysregulated upon transformation and identify potential predictors and potential therapeutic vulnerabilities of NE transformation in the lung. See related commentary by Meador and Lovly, p. 2962. This article is highlighted in the In This Issue feature, p. 2945.

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation

Project description:Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Upregulation of the cell cycle kinase CDC7 occurred in tumors undergoing NE transformation, after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of MYC, implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a strategy to constrain lineage plasticity and to effectively treat NE tumors. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk.

2024-05-12 | GSE265887 | GEO

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation II

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CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation I

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Cell of origin defines epigenetic mechanisms of transformation

Project description:Cell of origin defines epigenetic mechanisms of transformation

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A multiomic analysis of Waldenström macroglobulinemia defines distinct disease subtypes

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