Ribociclib mitigates cisplatin-associated kidney injury through retinoblastoma-1 dependent mechanisms

Kim, Ji Young; Jayne, Laura A.; Bai, Yuntao; Feng, Mei; Clark, Matthew A.; Chung, Sangwoon; Christman, John W.; Cianciolo, Rachel E.; Pabla, Navjotsingh

doi:10.1016/j.bcp.2020.113939

Cited by 22 publications

(18 citation statements)

References 61 publications

(97 reference statements)

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“…Given that a progressive decline in FECH activity preceded the development of AKI at 2 weeks, we questioned if FECH knockdown would influence vemurafenib nephrotoxicity. Using hydrodynamic siRNA injection approach 46,47 , we identified a specific siRNA that reduced FECH protein expression by ~70% ( Fig. 5A-B ).…”

Section: Resultsmentioning

confidence: 99%

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition

Bai¹,

Kim²,

Jayne³

et al. 2021

Preprint

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A multitude of disease and therapy related factors drive the frequent development of renal disorders in cancer patients. Along with chemotherapy, the newer targeted therapeutics can also cause renal dysfunction through on and off-target mechanisms. Interestingly, among the small-molecule inhibitors approved for the treatment of cancers that harbor BRAF-kinase activating mutations, vemurafenib can trigger tubular damage and acute kidney injury (AKI). To investigate the underlying mechanisms, here, we have developed cell culture and mouse models of vemurafenib nephrotoxicity. Our studies show that at clinically relevant concentrations vemurafenib induces cell-death in transformed and primary murine and human renal tubular epithelial cells (RTEC). In mice, two weeks of daily vemurafenib treatment causes moderate AKI with histopathological characteristics of RTEC injury. Importantly, RTEC-specific BRAF gene deletion did not influence renal function under normal conditions or alter the severity of vemurafenib-associated renal impairment. Instead, we found that inhibition of ferrochelatase (FECH), an enzyme involved in heme biosynthesis contributes to vemurafenib nephrotoxicity. FECH overexpression protected RTECs and conversely FECH knockdown increased the sensitivity to vemurafenib nephrotoxicity. Collectively, these studies suggest that vemurafenib-associated RTEC dysfunction and nephrotoxicity is BRAF-independent and caused in part by off-target FECH inhibition.Translational StatementBRAF is the most frequently mutated protein kinase and a critical oncogenic driver in human cancers. In melanoma and other cancers with BRAF activating mutations, BRAF targeted small-molecule therapeutics such as vemurafenib, and dabrafenib have shown remarkable clinical benefits. However, recent clinical studies have shown that a significant number of patients that receive vemurafenib develop AKI through mechanisms that remain unknown. The present study describes the development of novel experimental models of vemurafenib nephrotoxicity and reveals the underlying off-target mechanisms that contribute to renal injury.

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Section: Resultsmentioning

confidence: 99%

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition

Bai¹,

Kim²,

Jayne³

et al. 2021

Preprint

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“…The cytoprotective effects of ribociclib are likely dependent on the maintenance of Rb1 in a hypophosphorylated and functionally active form under stress conditions. 9 And; in another animal study by Pabla et al, ribociclib can prevent cisplatin induced AKI by inhibiting two relevant targets; renal cellcycle progression and organic cation transporter 2, a renal uptake transporter of cisplatin. 10 Another CDK 4/6 inhibitor Abemaciclib inhibits renal efflux transporters such as, MATE-1 and 2-K, and consequently inhibits creatinine secretion into the renal tubule.…”

Section: Discussionmentioning

confidence: 99%

Ribociclib induced acute kidney injury: A case report

Gültürk

Yılmaz

Özmen

et al. 2021

J Oncol Pharm Pract

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Introduction Among females, breast cancer is the most common type of cancer. Hormon receptor positive (HR+) subtype constitutes 75% of the diagnosed breast cancers. Combination of the cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and endocrine therapy significantly improves overall survival and progression-free survival. Ribociclib is an oral CDK 4/6 inhibitor and some adverse effects are identified. According to MONALEESA 2-3-7 studies, no adverse effect (AE) were reported due to grade 3 or 4 acute kidney injury (AKI) that caused treatment discontinuation. Case report We report a ribociclib-induced grade 3 AKI in an elderly woman who was treated for metastatic breast cancer. During first cycle of therapy, she was admitted to the oncology clinic with diagnosis of AKI. Management and outcome: Ribociclib treatment was discontinued and secondary causes of AKI were excluded. During the follow-up, kidney function values returned to the normal range spontaneously. Ribociclib treatment was re-initiated by reducing the dose (400 mg daily). Despite dose reduction; grade 3 AKI recurred when ribociclib was re-initiated and the drug was permanently discontinued. Discussion According to MONALEESA 2-3-7 studies; no AE were reported due to grade 3 or 4 AKI. Despite these studies, the FDA reported that 20% of patients with ribociclib + letrozole combination therapy may have any stage elevation of creatinine. Ribociclib induced creatinine elevations are generally mild (grade 1–2) and can be managed by dose reduction or close monitoring of creatinine levels. We report the first case of grade 3 AKI that caused treatment discontinuation following administration of ribociclib.

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“…Animal models of acute kidney injury. We carried out all the studies presented here in age-matched male mice at 8-12 weeks of age using methods described in our recent studies (31,62,63). In all the studies with conditional Vgf and Sox9 knockout mice, we used male littermates from mice bred inhouse.…”

Section: Methodsmentioning

confidence: 99%

SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in renal tubular epithelial cells

Kim

Bai

Jayne

et al. 2020

Journal of Biological Chemistry

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Acute kidney injury (AKI) is a common clinical condition associated with diverse etiologies and abrupt loss of renal function. In patients with sepsis, rhabdomyolysis, cancer, as well as cardiovascular disorders, the underlying disease or associated therapeutic interventions can cause hypoxia, cytotoxicity, and inflammatory insults to renal tubular epithelial cells (RTECs) resulting in the onset of AKI. To uncover stress-responsive disease-modifying genes, here we have carried out renal transcriptome profiling in three distinct murine models of AKI. We find that Vgf nerve growth factor inducible gene upregulation is a common transcriptional stress response in RTECs to ischemia, cisplatin, and rhabdomyolysis-associated renal injury. The Vgf gene encodes a secretory peptide precursor protein that has critical neuro-endocrine functions; however, its role in the kidneys remains unknown. Our functional studies show that RTEC-specific Vgf gene ablation exacerbates ischemia, cisplatin, and rhabdomyolysis-associated AKI in vivo and cisplatin-induced RTEC cell death in vitro. Importantly, aggravation of cisplatin-induced renal injury caused by Vgf gene ablation is partly reversed by TLQP-21, a Vgf-derived peptide. Finally, in vitro and in vivo mechanistic studies showed that injury-induced Vgf upregulation in RTECs is driven by the transcriptional regulator Sox9. These findings reveal a crucial downstream target of the Sox9-directed transcriptional program and identify Vgf as a stress-responsive protective gene in kidney tubular epithelial cells.

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Ribociclib mitigates cisplatin-associated kidney injury through retinoblastoma-1 dependent mechanisms

Cited by 22 publications

References 61 publications

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition

Nephrotoxicity of the BRAF-kinase inhibitor Vemurafenib is driven by off-target Ferrochelatase inhibition

Ribociclib induced acute kidney injury: A case report

SOX9 promotes stress-responsive transcription of VGF nerve growth factor inducible gene in renal tubular epithelial cells

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