IGF1R Contributes to Cell Proliferation in ALK-Mutated Neuroblastoma with Preference for Activating the PI3K-AKT Signaling Pathway

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Abstract
Aberrant activation of anaplastic lymphoma kinase (ALK) by activating point mutation or amplification drives 5–12% of neuroblastoma (NB). Previous work has identified the involvement of the insulin-like growth factor 1 receptor (IGF1R) receptor tyrosine kinase (RTK) in a wide range of cancers. We show here that many NB cell lines exhibit IGF1R activity, and that IGF1R inhibition led to decreased cell proliferation to varying degrees in ALK-driven NB cells. Furthermore, combined inhibition of ALK and IGF1R resulted in synergistic anti-proliferation effects, in particular in ALK-mutated NB cells. Mechanistically, both ALK and IGF1R contribute significantly to the activation of downstream PI3K-AKT and RAS-MAPK signaling pathways in ALK-mutated NB cells. However, these two RTKs employ a differential repertoire of adaptor proteins to mediate downstream signaling effects. We show here that ALK signaling led to activation of the RAS-MAPK pathway by preferentially phosphorylating the adaptor proteins GAB1, GAB2, and FRS2, while IGF1R signaling preferentially phosphorylated IRS2, promoting activation of the PI3K-AKT pathway. Together, these findings reveal a potentially important role of the IGF1R RTK in ALK-mutated NB and that co-targeting of ALK and IGF1R may be advantageous in clinical treatment of ALK-mutated NB patients.
Funding Information
  • Swedish Childhood Cancer Foundation (JG: TJ2016-0088, PR2016-0011, PR2019-0118, RHP: PR2022-0029, BH: PR2021-0027, JG: 32170719, RHP CAN21/1549, BH CAN21/1525, RHP: 2019-03914, BH: 2021-1192, RB13-0204, RHP2016, KAW 2018.0057)
  • National Natural Science Foundation of China (JG: TJ2016-0088, PR2016-0011, PR2019-0118, RHP: PR2022-0029, BH: PR2021-0027, JG: 32170719, RHP CAN21/1549, BH CAN21/1525, RHP: 2019-03914, BH: 2021-1192, RB13-0204, RHP2016, KAW 2018.0057)
  • Swedish Cancer Society (JG: TJ2016-0088, PR2016-0011, PR2019-0118, RHP: PR2022-0029, BH: PR2021-0027, JG: 32170719, RHP CAN21/1549, BH CAN21/1525, RHP: 2019-03914, BH: 2021-1192, RB13-0204, RHP2016, KAW 2018.0057)
  • Swedish Research Council (JG: TJ2016-0088, PR2016-0011, PR2019-0118, RHP: PR2022-0029, BH: PR2021-0027, JG: 32170719, RHP CAN21/1549, BH CAN21/1525, RHP: 2019-03914, BH: 2021-1192, RB13-0204, RHP2016, KAW 2018.0057)
  • Stiftelsen för Strategisk Forskning (JG: TJ2016-0088, PR2016-0011, PR2019-0118, RHP: PR2022-0029, BH: PR2021-0027, JG: 32170719, RHP CAN21/1549, BH CAN21/1525, RHP: 2019-03914, BH: 2021-1192, RB13-0204, RHP2016, KAW 2018.0057)
  • Göran Gustafssons Stiftelse för Naturvetenskaplig och Medicinsk Forskning (JG: TJ2016-0088, PR2016-0011, PR2019-0118, RHP: PR2022-0029, BH: PR2021-0027, JG: 32170719, RHP CAN21/1549, BH CAN21/1525, RHP: 2019-03914, BH: 2021-1192, RB13-0204, RHP2016, KAW 2018.0057)
  • Knut och Alice Wallenbergs Stiftelse (JG: TJ2016-0088, PR2016-0011, PR2019-0118, RHP: PR2022-0029, BH: PR2021-0027, JG: 32170719, RHP CAN21/1549, BH CAN21/1525, RHP: 2019-03914, BH: 2021-1192, RB13-0204, RHP2016, KAW 2018.0057)

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