DUSP6 is transcriptionally upregulated by activated ALK and cooperates with ALK signaling to reduce lorlatinib sensitivity in neuroblastoma cells

Thompson, E.; Patel, V.; Karapouliou, C.; Rajeeve, V.; Cutillas, P.; Stoker, A.

doi:10.64898/2026.06.07.730727

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bioRxiv · 10.64898/2026.06.07.730727

DUSP6 is transcriptionally upregulated by activated ALK and cooperates with ALK signaling to reduce lorlatinib sensitivity in neuroblastoma cells

Thompson, E.·Patel, V.·Karapouliou, C.·Rajeeve, V.·Cutillas, P.·Stoker, A.

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Abstract

Neuroblastoma is a pediatric, sympathoadrenal tumour accounting for 7-10% of childhood malignancies. Some neuroblastomas are driven by activating mutations in ALK kinase and inhibitors show promise in clinical trials. Nevertheless, with resistance an ever-present concern, it remains important to understand better the effectors and modulators of ALK signaling. Wild type ALK promotes ERK activation, raising expression of negative regulators such as the dual-specificity phosphatase (DUSP) DUSP6. DUSP6 though can be pro- or anti-oncogenic in different cancers and its role in neuroblastoma cells remains unclear. We sought to understand its role in cells with either wild type or mutated ALK. Mutated ALK strongly promotes DUSP6 transcription, but apparently not through the ERK pathway. DUSP6 also appears to promote neuroblastoma cell proliferation without affecting ERK. Additionally, when DUSP6 is lost, the cells become more sensitive to ALK inhibitors lorlatinib and crizotinib. Phosphoproteomic analysis of such cells demonstrates that mutated ALK cooperates with DUSP6 to maximise signaling through several potential pathways, but again not through ERK or AKT. Their cooperation may also maintain optimal levels of N-Myc in MYCN-amplified neuroblastoma cells. While key substrates of DUSP6 remain to be determined in neuroblastoma cells, our study defines a novel role for this phosphatase in supporting the action of oncogenic ALK.

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Thompson, E., Patel, V., Karapouliou, C., Rajeeve, V., Cutillas, P., Stoker, A.. 2026-06-11. DUSP6 is transcriptionally upregulated by activated ALK and cooperates with ALK signaling to reduce lorlatinib sensitivity in neuroblastoma cells. https://doi.org/10.64898/2026.06.07.730727

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