The kinase ALK stimulates the kinase ERK5 to promote the expression of the oncogene MYCN in neuroblastoma

Abstract

Anaplastic lymphoma kinase (ALK) is an important molecular target in neuroblastoma. Although tyrosine kinase inhibitors abrogating ALK activity are currently in clinical use for the treatment of ALK-positive (ALK(+)) disease, monotherapy with ALK tyrosine kinase inhibitors may not be an adequate solution for ALK(+) neuroblastoma patients. Increased expression of the gene encoding the transcription factor MYCN is common in neuroblastomas and correlates with poor prognosis. We found that the kinase ERK5 [also known as big mitogen-activated protein kinase (MAPK) 1 (BMK1)] is activated by ALK through a pathway mediated by phosphoinositide 3-kinase (PI3K), AKT, MAPK kinase kinase 3 (MEKK3), and MAPK kinase 5 (MEK5). ALK-induced transcription of MYCN and stimulation of cell proliferation required ERK5. Pharmacological or RNA interference-mediated inhibition of ERK5 suppressed the proliferation of neuroblastoma cells in culture and enhanced the antitumor efficacy of the ALK inhibitor crizotinib in both cells and xenograft models. Together, our results indicate that ERK5 mediates ALK-induced transcription of MYCN and proliferation of neuroblastoma, suggesting that targeting both ERK5 and ALK may be beneficial in neuroblastoma patients.

Brigatinib, an anaplastic lymphoma kinase inhibitor, abrogates activity and growth in ALK positive neuroblastoma cells, Drosophila and mice

“…D. Average body weight on the day at which mice were sacrificed after 14 days treatment with either brigatinib or vehicle control (p=0. downstream targets of ALK such as ERK5 [35], AKT and ERK1/2 were clearly less phosphorylated upon treatment with brigatinib [7,35]. MYCN amplification is associated with poor prognosis in NB patients, and there is evidence to the effect that MYCN cooperates with ALK in a synergistic manner to promote tumor growth [34].…”

“…In order to investigate the therapeutic efficacy of brigatinib in a neuroblastoma setting we employed several neuroblastoma cell lines, including CLB-BAR (MYCN amplification, ALK (Δ4-11) and amplified, ALK addicted), CLB-GE (MYCN amplification, ALK (F1174V) amplification, ALK addicted), IMR32 (MYCN amplification, WT ALK) and CLB-PE (MYCN amplified, WT ALK) [21,[31][32][33]. We have earlier shown that both CLB-BAR and CLB-GE cell lines are ALK addicted, while IMR32 and CLB-PE are not [34,35]. ALK addicted cell lines were treated with either brigatinib or crizotinib, as a positive control for ALK inhibition, and their effect on ALK signaling analyzed by immunoblotting ( Figure 1A, 1B).…”

Neuronal leucine-rich repeat 1 negatively regulates anaplastic lymphoma kinase in neuroblastoma

“…Conversely, MYCN also transactivates ALK 43, and ALK signalling promotes MYCN transcription through activation of ERK544. Thus, both NLRR1 and ALK form positive feedback loops with MYCN.…”

The MEK5/ERK5 signalling pathway in cancer: a promising novel therapeutic target

“…MEK5/ERK5 inhibition has been revealed to have a significant influence on the sensitisation of cancer cells to chemotherapy agents, justifying the potential of MEK5/ERK5 inhibitors for future clinical use. Inhibition of ERK5 sensitised tumour cells to etoposide [40], trastuzumab [26], fulvestrant [31], tamoxifen [31], docetaxel [27,28], doxorubicin [28,94,100,103], cisplatin [27,100], vinorelbine [27], imatinib [106], dexamethasone [19], bortezomib [19], cytarabine [73], and crizotinib [97]. It has also been demonstrated that ERK5 inhibition, either through pharmacological or genetic approaches, leads to tumour cell sensitisation to 5-FU [61].…”

“…In this regard, ERK5 activation has been recently demonstrated to be crucial in the ALK-induced transcription of MYCN and consequent promotion of aberrant proliferation of neuroblastoma cells. Interestingly, the inhibition of ERK5, by genetic or pharmacological approaches, enhanced the antitumour efficacy of crizotinib in both in vitro and in vivo models [97], supporting the therapeutic efficacy of targeting ERK5 in neuroblastoma. Moreover, ERK5 signalling pathway effectors also appear at the top of the list of deregulated molecules in bladder cancer [98], and miRNA-143 overexpression, with concomitant repression of ERK5, functions as a tumour suppressor in human bladder cancer [99].…”