Lambertz I, Kumps C, Claeys S, Lindner S, Beckers A, Janssens E, Carter DR, Cazes A, Cheung BB, De Mariano M, De Bondt A, De Brouwer S, Delattre O, Gibbons J, Janoueix-Lerosey I, Laureys G, Liang C, Marchall GM, Porcu M, Takita J, Trujillo DC, Van Den Wyngaert I, Van Roy N, Van Goethem A, Van Maerken T, Zabrocki P, Cools J, Schulte JH, Vialard J, Speleman F, De Preter K. Clin Cancer Res. 2015 Jul 15;21(14):3327-39. PMID:25805801
Single-molecule therapies almost invariably lead to resis- tance due to oncogene switching and modulation of various regulatory loops. Therefore, a deeper understanding of the nature and plasticity of targeted pathways is required to identify fragile nodes that may act as additional targets for combination therapies and to design robust and sustainable treatment strategies. In this study, we established and validat- ed a 77-gene ALK signature in ALK-mutant neuroblastomas. We identified a strong upregulation of MAPK-negative feed- back regulators. While this did not render the cells more sensitive to MEK inhibitors, ablation of negative feedback regulation upon ALK inhibition can affect other signaling axes within the mutant cells and should be taken into account when monitoring the molecular effects of such treatment or treatment failure. Next, we also discovered mutant ALK upre- gulation of RET and RET-driven cholinergic markers offering novel opportunities for testing ALK-RET oriented molecular combination therapies.