ALK signaling primes the DNA damage response sensitizing ALK- driven neuroblastoma to therapeutic ATR inhibition

• 成果类型: Article
• 署名作者: Borenas, Marcus; Umapathy, Ganesh; Lind, Dan E.; Lai, Wei -Yun; Guan, Jikui; Johansson, Joel; Jennische, Eva; Schmidt, Alexander; Kurhe, Yeshwant; Gabre, Jonatan L.; Aniszewska, Agata; Stromberg, Anneli; Bemark, Mats; Hall, Michael N.; Van den Eynden, Jimmy; Hallberg, Bengt; Palmer, Ruth H.
• 署名单位: University of Gothenburg; Ghent University; University of Gothenburg; Sahlgrenska University Hospital; University of Basel
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14477
• DOI: 10.1073/pnas.2315242121
• 发表日期: 2024-01-02
• 关键词: kinase; chk1; mycn; phosphorylation; differentiation; chemotherapy; combination; landscape; reveals; cells

摘要

High -risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high -risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3- related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14- d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14- d combined ATR/ ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high -risk patient groups with oncogene- induced replication stress.