Abstract B038: Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib

Abstract

Abstract The RAS-RAF-MEK-ERK pathway is a major player in initiation and progression of multiple cancers where it can be hyper-activated by upstream regulatory proteins, such as tyrosine kinases, phosphatases, and GTPases. Several inhibitors targeting the RAS-MAPK pathway exhibit anticancer activity and are approved as single agent in specific cancers. One such is the MEK inhibitor trametinib, which is included as a rational poly therapy strategy for treating EML4-ALK, EGFR, and K-RAS mutant lung cancer and neuroblastoma containing hyper-activating RAS-MAPK pathway mutations. In neuroblastoma, a heterogeneous disease, relapse cases display an increased rate of mutations of ALK, NRAS, NF1 genes, leading to hyper-activation of RAS-MAPK signaling. Targeting the RAS-MAPK pathways offers attractive options for combinatorial treatment together with ALK inhibitors, since monotreatment has not yet produced strong clinical results in ALK-positive neuroblastoma patients. Here we investigate the response of ALK-positive neuroblastoma cell lines to MEK inhibition, employing trametinib. We show that pharmacologic inhibition of the MEK-ERK pathway in ALK-positive neuroblastoma cells results in increased levels of activation/phosphorylation of AKT and ERK5. This feedback response is regulated by the mTORC2 complex protein SIN1. Taken together, our results indicate that blocking MEK-ERK leads to "increased activation" of AKT signalling core in ALK-positive neuroblastoma, intensifying survival signals in these cells. Our results contraindicate use of MEK inhibitors as effective single and poly-therapeutic strategy in ALK-positive neuroblastoma. Citation Format: Bengt Hallberg, Ganesh Umapathy, Diana Cervantes-Madrid, Jikui Guan, Dan E. Gustafsson, Ruth H. Palmer. Anaplastic lymphoma kinase addicted neuroblastoma cell lines are associated with growth upon treatment with MEK inhibitor trametinib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B038.