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Updated: Aug 26, 2025
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Validation of a non-oncogene encoded vulnerability to exportin 1 inhibition in pediatric renal tumors
Diego F Coutinho1, Prabhjot S Mundi2, Lianna J Marks3
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Background:
Malignant rhabdoid tumors (MRTs) and Wilms' tumors (WTs) are rare and aggressive renal tumors of infants and young children comprising ∼5% of all pediatric cancers. MRTs are among the most genomically stable cancers, and although WTs are genomically heterogeneous, both generally lack therapeutically targetable genetic mutations.
Methods:
Comparative protein activity analysis of MRTs (n = 68) and WTs (n = 132) across TCGA and TARGET cohorts, using metaVIPER, revealed elevated exportin 1 (XPO1) inferred activity. In vitro studies were performed on a panel of MRT and WT cell lines to evaluate effects on proliferation and cell-cycle progression following treatment with the selective XPO1 inhibitor selinexor. In vivo anti-tumor activity was assessed in patient-derived xenograft (PDX) models of MRTs and WTs.
Findings:
metaVIPER analysis identified markedly aberrant activation of XPO1 in MRTs and WTs compared with other tumor types. All MRT and most WT cell lines demonstrated baseline, aberrant XPO1 activity with in vitro sensitivity to selinexor via cell-cycle arrest and induction of apoptosis. In vivo, XPO1 inhibitors significantly abrogated tumor growth in PDX models, inducing effective disease control with sustained treatment. Corroborating human relevance, we present a case report of a child with multiply relapsed WTs with prolonged disease control on selinexor.
Conclusions:
We report on a novel systems-biology-based comparative framework to identify non-genetically encoded vulnerabilities in genomically quiescent pediatric cancers. These results have provided preclinical rationale for investigation of XPO1 inhibitors in an upcoming investigator-initiated clinical trial of selinexor in children with MRTs and WTs and offer opportunities for exploration of inferred XPO1 activity as a potential predictive biomarker for response.
Funding:
This work was funded by CureSearch for Children's Cancer, Alan B. Slifka Foundation, NIH (U01 CA217858, S10 OD012351, and S10 OD021764), Michael's Miracle Cure, Hyundai Hope on Wheels, Cannonball Kids Cancer, Conquer Cancer the ASCO Foundation, Cycle for Survival, Paulie Strong Foundation, and the Grayson Fund.
Insights
Malignant rhabdoid tumors (MRTs) and Wilms' tumors (WTs) show high exportin 1 (XPO1) activity. Targeting XPO1 with selinexor demonstrated significant anti-tumor effects in preclinical models and a patient case, suggesting a new therapeutic strategy for these rare pediatric cancers.
Area of Science:
- Utilizing a systems-biology approach to analyze pediatric renal tumors.
- Investigating protein activity and therapeutic vulnerabilities in rare cancers.
Background:
- Malignant rhabdoid tumors (MRTs) and Wilms' tumors (WTs) are rare, aggressive pediatric renal cancers.
- These tumors generally lack targetable genetic mutations, posing treatment challenges.
Observation:
- Comparative protein activity analysis revealed significantly elevated exportin 1 (XPO1) inferred activity in MRTs and WTs.
- Both MRT and most WT cell lines exhibited baseline aberrant XPO1 activity.
- In vitro studies showed sensitivity to the selective XPO1 inhibitor selinexor, leading to cell-cycle arrest and apoptosis.
Findings:
- In vivo studies using patient-derived xenograft (PDX) models demonstrated that XPO1 inhibitors significantly reduced tumor growth.
- Effective disease control was achieved with sustained XPO1 inhibitor treatment in preclinical models.
- A case report highlighted prolonged disease control in a child with relapsed WTs treated with selinexor.
Implications:
- The findings provide a preclinical rationale for investigating XPO1 inhibitors, such as selinexor, in a clinical trial for pediatric MRTs and WTs.
- Inferred XPO1 activity may serve as a predictive biomarker for treatment response in these cancers.
- This study identifies a novel therapeutic strategy targeting non-genetically encoded vulnerabilities in genomically quiescent pediatric cancers.
