Abstract LB-C24: Resistance to ALK inhibition is associated with enhanced BRD4 dependence in ALK-mutated MYCN-amplified neuroblastoma

Abstract

Abstract Despite substantial therapeutic advances, the long-term survival rate of patients with high-risk neuroblastoma (NB), a tumor of the peripheral sympathetic nervous system is still dismal. Activating mutations in the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase represent promising therapeutic targets in this disease and have prompted clinical trials of ALK inhibitors. But as with all molecularly targeted therapies, resistance is inevitable and will limit the ultimate utility of this therapeutic strategy. To elucidate the mechanisms of resistance to ALK inhibitors, we have generated isogenic NB cells, expressing the tumorigenic ALKF1174L mutation and amplified MYCN, with acquired resistance to the ALK inhibitor TAE684, through continuous exposure of increasing concentrations of the compound over time. We found that resistance was associated with downregulation of ALK activity, thus ruling out secondary mutations as a mechanism of resistance, and interestingly the other major oncogenic driver in neuroblastoma, MYCN, was downregulated as well. A comparative genome-wide expression analysis revealed global transcriptional downregulation in the resistant cells, as compared with their parental sensitive counterparts, in accordance with the aforementioned MYCN downregulation, as MYCN is known to act as a transcriptional amplifier in MYCN-amplified NB cells. Additionally, these resistant cells exhibited a 10-fold increased sensitivity to the BRD4 inhibitor JQ1, compared to sensitive cells, and MYCN as well as global gene expression were rescued after treatment. These results strongly suggest that resistance to ALK inhibition in ALKF1174L MYCN-amplified NB cells leads to a MYCN-independent enhanced BRD4 dependence, therefore providing a rationale for the use of BET inhibitors to overcome such resistance. Studies are currently underway to characterize the unique epigenetic landscape driving the resistant cells' survival and therefore identify novel targets that could be taken advantage of in future therapeutic strategies. Citation Format: David Debruyne, Bandana Sharma, Nathanael Gray, Rani George. Resistance to ALK inhibition is associated with enhanced BRD4 dependence in ALK-mutated MYCN-amplified neuroblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C24.