Abstract C159: ALK signaling primes the DNA damage response allowing exploitation of ATR inhibition in ALK-driven Neuroblastoma

Abstract High-risk neuroblastoma currently presents significant clinical challenges. Oncogenes such as MYCN and ALK, which are often involved in high-risk neuroblastoma, result in increased replication stress in cancer cells, offering therapeutically exploitable options. We previously identified an ATR/ALK inhibitor combination as an effective therapeutic approach in two independent genetically modified mouse neuroblastoma models. Here we show that ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. Remarkably, 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 ALKi/ATRi combination treatment that resulted in robust and sustained responses. Here, we describe the mechanism underlying the remarkable tumor response to combined ATR/ALK inhibition. Our results identify a unique ability of ATR inhibition to trigger tumor regression in neuroblastoma and underscore the importance of further exploring combined ALK/ATR inhibition in neuroblastoma, particularly in high-risk patient groups with oncogene-induced replication stress. Citation Format: Marcus Borenäs, Ganesh Umapathy, Dan E. Lind, Wei-Yun Lai, Jikui Guan, Joel Johansson, Eva Jennische, Alexander Schmidt, Jonatan Gabre, Mats Bemark, Michael N. Hall, Jimmy Van den Eynden, Bengt Hallberg, Ruth H. Palmer. ALK signaling primes the DNA damage response allowing exploitation of ATR inhibition in ALK-driven Neuroblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C159.