DNA damage is overcome by TRIP13 overexpression during cisplatin nephrotoxicity

Hama, Taketsugu; Nagesh, Prashanth K.B.; Chowdhury, Pallabita; Moore, Bob M.; Yallapu, Murali M.; Regner, Kevin R.; Park, Frank

doi:10.1172/jci.insight.139092

Cited by 10 publications

(5 citation statements)

References 63 publications

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“…While the role of p53 in response to KPT-330 has been previously reported 62 , we identified that suppression or inhibition of nuclear export leads to suppression of TRIP13 in FHWT. We find that although TRIP13 is traditionally thought to affect G2/M 50 , 63 , loss of TRIP13 affects both G1 and G2/M in FHWT (Fig. 4 ).…”

Section: Discussionmentioning

confidence: 66%

Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin

Mittal,

Cooper,

Lee

et al. 2024

Commun Biol

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Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

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Section: Discussionmentioning

confidence: 66%

Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin

Mittal,

Cooper,

Lee

et al. 2024

Commun Biol

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show abstract

“…While the role of TP53 in response to KPT-330 has been previously reported 52 , we identified that suppression or inhibition of nuclear export leads to suppression of TRIP13 in FHWT. We find that although TRIP13 is traditionally thought to affect G2/M 53,54 , loss of TRIP13 affects both G1 and G2/M in FHWT. Furthermore, when we compare the differentially expressed genes between KPT-330 treated cells as compared to cells with TRIP13 suppression, we find several potential tumor suppressors (e.g.…”

Section: Kpt-330 and Doxorubicin Are Synergistic In Vitro And In Vivo...mentioning

confidence: 61%

Targeting TRIP13 in Wilms Tumor with Nuclear Export Inhibitors

Mittal

Lee

Cooper

et al. 2022

Preprint

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Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies in a systematic manner remains challenging in part due to the lack of faithful preclinical in vitro models. We established ten short-term patient-derived WT cell lines and characterized these models using low-coverage whole genome sequencing, whole exome sequencing and RNA-sequencing, which demonstrated that these ex-vivo models faithfully recapitulate WT biology. We then performed targeted RNAi and CRISPR-Cas9 loss-of-function screens and identified the nuclear export genes (XPO1 and KPNB1) as strong vulnerabilities. We observed that these models are sensitive to nuclear export inhibition using the FDA approved therapeutic agent, selinexor (KPT-330). Selinexor treatment of FHWT suppressed TRIP13 expression, which was required for survival. We further identified in vitro and in vivo synergy between selinexor and doxorubicin, a chemotherapy used in high risk FHWT. Taken together, we identified XPO1 inhibition with selinexor as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

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“…Cisplatin-induced AKI (CP-AKI) is commonly observed in the clinic, and it is also widely used in laboratory investigations to explore the pathogenesis of renal injuries. The molecular machinery of AKI is quite complicated, previous publications have revealed various aspects of mechanisms in CP-AKI, such as DNA damage, mitochondrial disruption, vascular disorder, and ferroptosis [ 4 , [32] , [33] , [34] ]. Despite decades of intensive investigation, the exact mechanism of CP-AKI still remains blurry.…”

Section: Discussionmentioning

confidence: 99%