Neratinib is a TFEB and TFE3 activator that potentiates autophagy and unbalances energy metabolism in ERBB2+ breast cancer cells

Bellese, Grazia; Tagliatti, Erica; Gagliani, Maria Cristina; Santamaria, Sara; Arnaldi, Pietro; Falletta, Paola; Rusmini, P.; Matteoli, Michela; Castagnola, Patrizio; Cortese, Katia

doi:10.1016/j.bcp.2023.115633

Cited by 2 publications

(1 citation statement)

References 39 publications

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“…Neratinib enhanced autophagosome formation and could reduce receptor expression. Others have shown that neratinib can enhance macroautophagy and reduce receptor expression [24,25]. The present studies defined the biology of GZ17-6.02 in UM cells and in parallel determined its interaction with irreversible ERBB inhibitors (afatinib, neratinib) and with the cytotoxic agent doxorubicin.…”

Section: Introductionmentioning

confidence: 63%

GZ17-6.02 kills PDX isolates of uveal melanoma

Booth,

Roberts,

Spasojevic

et al. 2024

Oncotarget

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GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, overexpression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.

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Section: Introductionmentioning

confidence: 63%

GZ17-6.02 kills PDX isolates of uveal melanoma

Booth,

Roberts,

Spasojevic

et al. 2024

Oncotarget

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A NSC‐34 cell line‐derived spheroid model: Potential and challenges for in vitro evaluation of neurodegeneration

Arnaldi,

Casarotto,

Relucenti

et al. 2024

Microscopy Res & Technique

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Three‐dimensional (3D) spheroid models aim to bridge the gap between traditional two‐dimensional (2D) cultures and the complex in vivo tissue environment. These models, created by self‐clustering cells to mimic a 3D environment with surrounding extracellular framework, provide a valuable research tool. The NSC‐34 cell line, generated by fusing mouse spinal cord motor neurons and neuroblastoma cells, is essential for studying neurodegenerative diseases like amyotrophic lateral sclerosis (ALS), where abnormal protein accumulation, such as TAR‐DNA‐binding protein 43 (TDP‐43), occurs in affected nerve cells. However, NSC‐34 behavior in a 3D context remains underexplored, and this study represents the first attempt to create a 3D model to determine its suitability for studying pathology. We generated NSC‐34 spheroids using a nonadhesive hydrogel‐based template and characterized them for 6 days. Light microscopy revealed that NSC‐34 cells in 3D maintained high viability, a distinct round shape, and forming stable membrane connections. Scanning electron microscopy identified multiple tunnel‐like structures, while ultrastructural analysis highlighted nuclear bending and mitochondria alterations. Using inducible GFP‐TDP‐43‐expressing NSC‐34 spheroids, we explored whether 3D structure affected TDP‐43 expression, localization, and aggregation. Spheroids displayed nuclear GFP‐TDP‐43 expression, albeit at a reduced level compared with 2D cultures and generated both TDP‐35 fragments and TDP‐43 aggregates. This study sheds light on the distinctive behavior of NSC‐34 in 3D culture, suggesting caution in the use of the 3D model for ALS or TDP‐43 pathologies. Yet, it underscores the spheroids' potential for investigating fundamental cellular mechanisms, cell adaptation in a 3D context, future bioreactor applications, and drug penetration studies.Research Highlights 3D spheroid generation: NSC‐34 spheroids, developed using a hydrogel‐based template, showed high viability and distinct shapes for 6 days. Structural features: advanced microscopy identified tunnel‐like structures and nuclear and mitochondrial changes in the spheroids. Protein dynamics: the study observed how 3D structures impact TDP‐43 behavior, with altered expression but similar aggregation patterns to 2D cultures. Research implications: this study reveals the unique behavior of NSC‐34 in 3D culture, suggests a careful approach to use this model for ALS or TDP‐43 pathologies, and highlights its potential in cellular mechanism research and drug testing applications.

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Neratinib is a TFEB and TFE3 activator that potentiates autophagy and unbalances energy metabolism in ERBB2+ breast cancer cells

Cited by 2 publications

References 39 publications

GZ17-6.02 kills PDX isolates of uveal melanoma

GZ17-6.02 kills PDX isolates of uveal melanoma

A NSC‐34 cell line‐derived spheroid model: Potential and challenges for in vitro evaluation of neurodegeneration

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