1. CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation.
- Author
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Quintanal-Villalonga A, Kawasaki K, Redin E, Uddin F, Rakhade S, Durani V, Sabet A, Shafer M, Karthaus WR, Zaidi S, Zhan YA, Manoj P, Sridhar H, Kinyua D, Zhong H, Mello BP, Ciampricotti M, Bhanot UK, Linkov I, Qiu J, Patel RA, Morrissey C, Mehta S, Barnes J, Haffner MC, Socci ND, Koche RP, de Stanchina E, Molina-Pinelo S, Salehi S, Yu HA, Chan JM, and Rudin CM
- Subjects
- Humans, Male, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Cell Line, Tumor, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases antagonists & inhibitors, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Mice, Animals, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, Neuroendocrine Tumors metabolism, Neuroendocrine Tumors drug therapy, Proteolysis drug effects, Retinoblastoma Binding Proteins genetics, Retinoblastoma Binding Proteins metabolism, Ubiquitin-Protein Ligases, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms drug therapy, Lung Neoplasms genetics, Lung Neoplasms pathology, Lung Neoplasms metabolism, Lung Neoplasms drug therapy, Proto-Oncogene Proteins c-myc genetics, Proto-Oncogene Proteins c-myc metabolism
- Abstract
Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already 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 the MYC Proto-Oncogen (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 (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation., (© 2024. The Author(s).)
- Published
- 2024
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