Biomarker: der Weg zur individualisierten Therapie bei Nierenzelltumoren

Zeuschner, Philip; Zaccagnino, Angela; Junker, Kerstin

doi:10.1055/a-1517-6259

Cited by 2 publications

(3 citation statements)

References 69 publications

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“…For instance, cabozantinib activated ERK and completely hampered AKT signaling at the T308 and S473 sites only in the Caki-2 cell line, and these events were independent of pretreatment with sunitinib. On the contrary, the cabozantinib treatment schedule (alone or in sequence) of the 786-O cell line may affect the AKT signaling process, which is one of the most important pathways involved in cell proliferation, survival and transformation occurring in RCC tumorigenesis [ 10 , 76 ], as well as acquired resistance [ 77 ]. We observed that AKT was fully activated (phosphorylation at site S473 and T308) following cabozantinib exposure only in 786-O/S cells.…”

Section: Discussionmentioning

confidence: 99%

“…At present, therapeutic approaches used to treat patients with metastatic RCC (mRCC) are based on specific molecular characteristics that play an essential role in disease development [ 6 ]. In clear cell RCC (ccRCC, 80% of cases), the mutation of the tumor-suppressor von Hippel–Lindau ( VHL ) gene; chromosome remodeling by PBRM1 , BAP1 and SETD2 genes; hyperactivated PI3K/AKT pathways; and mTOR alterations are the main molecular features [ 7 , 8 , 9 , 10 ]. A loss of VHL elevates the stability of the hypoxia-inducible factor (HIF) transcription factor, which, in turn, tunes the expression of hypoxia-responsive genes, vascular endothelial growth factor (VEGF), platelet-derived growth factor beta (PDGF-β) and transforming growth factor (TGF-β) associated with both aberrant angiogenesis and tumor growth [ 11 , 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

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An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines

Zaccagnino

Vynnytska-Myronovska

Stöckle

et al. 2023

IJMS

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The tyrosine kinase inhibitor (TKI) cabozantinib might impede the growth of the sunitinib-resistant cell lines by targeting MET and AXL overexpression in metastatic renal cell carcinoma (mRCC). We studied the role of MET and AXL in the response to cabozantinib, particularly following long-term administration with sunitinib. Two sunitinib-resistant cell lines, 786-O/S and Caki-2/S, and the matching 786-O/WT and Caki-2/WT cells were exposed to cabozantinib. The drug response was cell-line-specific. The 786-O/S cells were less growth-inhibited by cabozantinib than 786-O/WT cells (p-value = 0.02). In 786-O/S cells, the high level of phosphorylation of MET and AXL was not affected by cabozantinib. Despite cabozantinib hampering the high constitutive phosphorylation of MET, the Caki-2 cells showed low sensitivity to cabozantinib, and this was independent of sunitinib pretreatment. In both sunitinib-resistant cell lines, cabozantinib increased Src-FAK activation and impeded mTOR expression. The modulation of ERK and AKT was cell-line-specific, mirroring the heterogeneity among the patients. Overall, the MET- and AXL-driven status did not affect cell responsiveness to cabozantinib in the second-line treatment. The activation of Src-FAK might counteract cabozantinib activity and contribute to tumor survival and may be considered an early indicator of therapy response.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines

Zaccagnino

Vynnytska-Myronovska

Stöckle

et al. 2023

IJMS

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“…

Renal cell carcinoma (RCC) represents the seventh predominant type of neoplasm in developed countries, accounting for about 2% of all diagnosed cancers worldwide. 1,2 Clear cell carcinoma (ccRCC) embodies the most common histological subtype (65%-70%) 3,4 and is characterised by mutation of the von Hippel-Lindau (VHL) tumour suppressor gene and chromatin remodelling genes (PBRM1, BAP1, and SETD2). 5 Mutations in VHL lead to stable activation of hypoxiainducible factor (HIF), which, in turn, upregulates vascular endothelial growth factor (VEGF), platelet-derived growth factor beta (PDGFβ) and transforming growth factor (TGFβ).

…”

mentioning

confidence: 99%

Molecular and functional characterization of reversible‐sunitinib‐tolerance state in human renal cell carcinoma

Zaccagnino,

Vynnytska‐Myronovska,

Stöckle

et al. 2024

J Cellular Molecular Medi

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Therapy failure with the tyrosine kinase inhibitor (TKI) sunitinib remains a great challenge in metastatic renal cell carcinoma (mRCC). Growing evidence indicates that the tumour subpopulation can enter a transient, non‐mutagenic drug‐tolerant state to endure the treatment underlying the minimal residual disease and tumour relapse. Drug tolerance to sunitinib remains largely unexplored in RCC. Here, we show that sunitinib‐tolerant 786‐O/S and Caki‐2/S cells are induced by prolonged drug treatment showing reduced drug sensitivity, enhanced clonogenicity, and DNA synthesis. Sunitinib‐tolerance developed via dynamic processes, including (i) engagement of c‐MET and AXL pathways, (ii) alteration of stress‐induced p38 kinase and pro‐survival BCL‐2 signalling, (iii) extensive actin remodelling, which was correlated with activation of focal adhesion proteins. Remarkably, the acute drug response in both sensitive and sunitinib‐tolerant cell lines led to dramatic fine‐tuning of the actin‐cytoskeleton and boosted cellular migration and invasion, indicating that the drug‐response might depend on cell state transition rather than pre‐existing mutations. The drug‐tolerant state was transiently acquired, as the cells resumed initial drug sensitivity after >10 passages under drug withdrawal, reinforcing the concept of dynamic regulation and phenotypic heterogeneity. Our study described molecular events contributing to the reversible switch into sunitinib‐tolerance, providing possible novel therapeutic opportunities in RCC.

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Biomarker: der Weg zur individualisierten Therapie bei Nierenzelltumoren

Cited by 2 publications

References 69 publications

An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines

An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines

Molecular and functional characterization of reversible‐sunitinib‐tolerance state in human renal cell carcinoma

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