Tyrosine kinase inhibitor-associated syndrome of inappropriate secretion of anti-diuretic hormone

Hill, Jordan; Shields, Jenna; Passero, Vida

doi:10.1177/1078155215592023

Cited by 15 publications

(9 citation statements)

References 7 publications

(11 reference statements)

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“…It is possible that this allows the kidney to fine-tune water balance more selectively. Although the effect of Src on AQP2 may be more predominant in the medulla, inhibition of Src with FDA-approved Src inhibitors such as dasatinib can cause syndrome of inappropriate secretion of anti-diuretic hormone (SIADH) (Hill et al 2016), a state of excessive water reabsorption secondary to AQP2 up-regulation and overexpression. In addition, fluid retention and hyponatraemia, an electrolyte imbalance caused by dysregulated retention of water by the kidney, is frequently reported as a common adverse effect of Src inhibitors in clinical trials (Brave et al 2008;Gold et al 2014;Schuetze et al 2017).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of non‐receptor tyrosine kinase Src induces phosphoserine 256‐independent aquaporin‐2 membrane accumulation

Cheung

Terlouw

Janssen

et al. 2018

The Journal of Physiology

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Key points Aquaporin‐2 (AQP2) is crucial for water homeostasis, and vasopressin (VP) induces AQP2 membrane trafficking by increasing intracellular cAMP, activating PKA and causing phosphorylation of AQP2 at serine 256, 264 and 269 residues and dephosphorylation of serine 261 residue on the AQP2 C‐terminus. It is thought that serine 256 is the master regulator of AQP2 trafficking, and its phosphorylation has to precede the change of phosphorylation state of other serine residues. We found that Src inhibition causes serine 256‐independent AQP2 membrane trafficking and induces phosphorylation of serine 269 independently of serine 256. This targeted phosphorylation of serine 269 is important for Src inhibition‐induced AQP2 membrane accumulation; without serine 269, Src inhibition exerts no effect on AQP2 trafficking. This result helps us better understand the independent pathways that can target different AQP2 residues, and design new strategies to induce or sustain AQP2 membrane expression when VP signalling is defective. Abstract Aquaporin‐2 (AQP2) is essential for water homeostasis. Upon stimulation by vasopressin, AQP2 is phosphorylated at serine 256 (S256), S264 and S269, and dephosphorylated at S261. It is thought that S256 is the master regulator of AQP2 trafficking and membrane accumulation, and that its phosphorylation has to precede phosphorylation of other serine residues. In this study, we found that VP reduces Src kinase phosphorylation: by suppressing Src using the inhibitor dasatinib and siRNA, we could increase AQP2 membrane accumulation in cultured AQP2‐expressing cells and in kidney collecting duct principal cells. Src inhibition increased exocytosis and inhibited clathrin‐mediated endocytosis of AQP2, but exerted its effect in a cAMP, PKA and S256 phosphorylation (pS256)‐independent manner. Despite the lack of S256 phosphorylation, dasatinib increased phosphorylation of S269, even in S256A mutant cells in which S256 phosphorylation cannot occur. To confirm the importance of pS269 in AQP2 re‐distribution, we expressed an AQP2 S269A mutant in LLC‐PK1 cells, and found that dasatinib no longer induced AQP2 membrane accumulation. In conclusion, Src inhibition causes phosphorylation of S269 independently of pS256, and induces AQP2 membrane accumulation by inhibiting clathrin‐mediated endocytosis and increasing exocytosis. We conclude that S269 can be phosphorylated without pS256, and pS269 alone is important for AQP2 apical membrane accumulation under some conditions. These data increase our understanding of the independent pathways that can phosphorylate different residues in the AQP2 C‐terminus, and suggest new strategies to target distinct AQP2 serine residues to induce membrane expression of this water channel when VP signalling is defective.

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Section: Discussionmentioning

confidence: 99%

Inhibition of non‐receptor tyrosine kinase Src induces phosphoserine 256‐independent aquaporin‐2 membrane accumulation

Cheung

Terlouw

Janssen

et al. 2018

The Journal of Physiology

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“…Hyponatremia is also frequently encountered in patients on TKIs, especially under sorafenib [53]. The underlying mechanism could be a syndrome of inappropriate secretion of antidiuretic hormone, but it should be pointed out that this effect can be paraneoplastic and developed independently of any treatment [94]. Digestive disorders, especially diarrhea, are frequent under TKIs and can also lead to hyponatremia.…”

Section: Electrolyte Disordersmentioning

confidence: 99%

Nephrotoxicity of Anti-Angiogenic Therapies

et al. 2021

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The use of inhibitors of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling for the treatment of cancer has increased over the last decade. This signaling pathway plays a fundamental role in angiogenesis and also in kidney physiology. The emergence of anti-angiogenic therapies has led to adverse nephrotoxic effects, despite improving the outcomes of patients. In this review, we will present the different anti-angiogenic therapies targeting the VEGFR pathway in association with the incidence of renal manifestations during their use. In addition, we will discuss, in detail, the pathophysiological mechanisms of frequent renal diseases such as hypertension, proteinuria, renal dysfunction, and electrolyte disorders. Finally, we will outline the cellular damage described following these therapies.

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“…To date, the best characterized mechanism of TKIassociated hyponatremia is SIADH. 30,31 Agents targeting v-Raf murine sarcoma viral oncogene homolog B (BRAF) have also been associated with hyponatremia. Sorafenib is a multikinase inhibitor of BRAF and c-Raf kinases and of the kinase domain of the vascular endothelial growth factor (VEGF) receptors 2 and 3, platelet-derived growth factor receptor, FLT3, p38 and c-Kit.…”

Section: Hyponatremia Associated With Tyrosine Kinase Inhibitors and mentioning

confidence: 99%

Cancer therapy-induced hyponatremia: A case-illustrated review

Pelletier

Škrtić

Kitchlu

2021

Journal of Onco-Nephrology

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Hyponatremia is the most common electrolyte disorder in patients with cancer and is associated with significant morbidity and mortality. Innovation in cancer therapies has led to substantial improvement in cancer outcomes, but also to new therapy-related toxicities, including electrolyte disturbance. Improvement in clinicians understanding of hyponatremia may mitigate adverse outcomes and improve quality of life in cancer patients. In this case-illustrated review, we discuss the mechanisms underlying drug-induced hyponatremia both in “classical” antineoplastic drugs and novel cancer therapies. Via these clinical cases, we describe hyponatremia caused by conventional chemotherapies (e.g. platinum compounds, vinca alkaloid, and alkylating agents) as well as hyponatremia related to tyrosine kinase inhibitors and other targeted therapies. We also focus on checkpoint inhibitors-induced hyponatremia, as these agents are increasingly used for a wide variety of malignancies. Lastly, we summarize therapy-related hyponatremia among recipients of newer treatments for multiple myeloma.

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Tyrosine kinase inhibitor-associated syndrome of inappropriate secretion of anti-diuretic hormone

Cited by 15 publications

References 7 publications

Inhibition of non‐receptor tyrosine kinase Src induces phosphoserine 256‐independent aquaporin‐2 membrane accumulation

Inhibition of non‐receptor tyrosine kinase Src induces phosphoserine 256‐independent aquaporin‐2 membrane accumulation

Nephrotoxicity of Anti-Angiogenic Therapies

Cancer therapy-induced hyponatremia: A case-illustrated review

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