Journal Article

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

Sabet, Amin, Linkov, Irina, Kawasaki, Kenta, Quintanal-Villalonga, Alvaro, Rakhade, Swanand, Karthaus, Wouter R., Salehi, Sohrab, Haffner, Michael C., Yu, Helena A., de Stanchina, Elisa, Uddin, Fathema, Redin, Esther, Mello, Barbara P., Molina-Pinelo, Sonia, Bhanot, Umesh K., Mehta, Sanjoy, Koche, Richard P., Ciampricotti, Metamia, Patel, Radhika A., Chan, Joseph M., Sridhar, Harsha, Shafer, Moniquetta, Manoj, Parvathy, Zhong, Hong, Socci, Nicholas D., Zhan, Yingqian A., Rudin, Charles M., Zaidi, Samir, Durani, Vidushi, Barnes, Jesse, Morrissey, Colm, Qiu, Juan, Kinyua, Dennis

2024

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 692/4028/67/1059/153 / 692/4028/67/1612 / 692/4028/67/589 / Animals / Cancer Research / Cell Biology / Cell culture / Cell cycle / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Cell division / Cell Line, Tumor / Cell Transformation, Neoplastic - genetics / Cell Transformation, Neoplastic - metabolism / Cisplatin / Clinical trials / Degradation / Genetic transformation / Humans / Internal Medicine / Irinotecan / Kinases / Lung carcinoma / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - metabolism / Lung Neoplasms - pathology / Male / Medicine / Medicine & Public Health / Mice / Myc protein / Neuroendocrine Tumors - drug therapy / Neuroendocrine Tumors - genetics / Neuroendocrine Tumors - metabolism / Neuroendocrine Tumors - pathology / Oncology / p53 Protein / Pathology / Phenotypes / Prostate / Prostate cancer / Prostate carcinoma / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / Proteasomes / Protein Serine-Threonine Kinases - antagonists & inhibitors / Protein Serine-Threonine Kinases - genetics / Protein Serine-Threonine Kinases - metabolism / Proteolysis - drug effects / Proto-Oncogene Proteins c-myc - genetics / Proto-Oncogene Proteins c-myc - metabolism / Retinoblastoma / Retinoblastoma Binding Proteins - genetics / Retinoblastoma Binding Proteins - metabolism / Small cell lung carcinoma / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism / Tumors / Ubiquitin-Protein Ligases