Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 23, Issue 18, Pages -Publisher
MDPI
DOI: 10.3390/ijms231810895
Keywords
neuroblastoma; doxorubicin; doxorubicin-resistance; TrkA; TrkAIII; tyrosine kinase inhibitors; ryanodine receptors; Ca2+ uniporter; calmodulin; Hsp90; cyclic hypoxia
Funding
- Department of Biotechnological and Applied Clinical Sciences of the University of L'Aquila [07_DG-2022_03, 07_DG-2022_08, 07_DG-2022_25]
Ask authors/readers for more resources
Patients with advanced neuroblastoma often develop resistance to the chemotherapy drug doxorubicin (Dox), leading to a poor prognosis. In this study, researchers identified a novel mechanism of Dox resistance involving the activation of an oncogenic variant called TrkAIII. They found that inhibiting this mechanism using certain kinase inhibitors could overcome Dox resistance. The study also provided insights into the molecular pathways and cellular processes involved in Dox-induced TrkAIII activation and resistance.
Patients with advanced neuroblastoma (NB) receive multimodal clinical therapy, including the potent anthracycline chemotherapy drug doxorubicin (Dox). The acquisition of Dox resistance, however, is a major barrier to a sustained response and leads to a poor prognosis in advanced disease states, reinforcing the need to identify and inhibit Dox resistance mechanisms. In this context, we report on the identification and inhibition of a novel Dox resistance mechanism. This mechanism is characterized by the Dox-induced activation of the oncogenic TrkAIII alternative splice variant, resulting in increased Dox resistance, and is blocked by lestaurtinib, entrectinib, and crizotinib tyrosine kinase and LY294002 IP3-K inhibitors. Using time lapse live cell imaging, conventional and co-immunoprecipitation Western blots, RT-PCR, and inhibitor studies, we report that the Dox-induced TrkAIII activation correlates with proliferation inhibition and is CDK1- and Ca2+-uniporter-independent. It is mediated by ryanodine receptors; involves Ca2+-dependent interactions between TrkAIII, calmodulin and Hsp90; requires oxygen and oxidation; occurs within assembled ERGICs; and does not occur with fully spliced TrkA. The inhibitory effects of lestaurtinib, entrectinib, crizotinib, and LY294002 on the Dox-induced TrkAIII and Akt phosphorylation and resistance confirm roles for TrkAIII and IP3-K consistent with Dox-induced, TrkAIII-mediated pro-survival IP3K/Akt signaling. This mechanism has the potential to select resistant dormant TrkAIII-expressing NB cells, supporting the use of Trk inhibitors during Dox therapy in TrkAIII-expressing NBs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available