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Metastatic clear-cell renal cell carcinoma: a frequent NOTCH1 mutation predictive of response to anti-NOTCH1 CB-103 treatment.
- Source :
- Experimental Hematology & Oncology; 5/15/2023, Vol. 12 Issue 1, p1-6, 6p
- Publication Year :
- 2023
-
Abstract
- Background: Clear-cell renal cell carcinomas (ccRCCs) are malignant tumors with high metastatic potential and resistance to treatments occurs almost constantly. Compared to primary tumors, there are still limited genomic data that has been obtained from metastatic samples. Methods: We aimed to characterize metastatic ccRCC by way of whole-genome analyses of metastatic formalin-fixed samples, using OncoScan<superscript>®</superscript> technology. We identified a frequent, unexpected pL1575P NOTCH1 mutation which we set out to characterize for translational purposes. We thus implemented patient-derived xenografts from metastatic samples of human ccRCC to explore its clinical significance. Results: We showed that pL1575P NOTCH1 mutation was an activating mutation, leading to the expression of NOTCH1-intracellular domain-active fragments in both cancer cells and tumor endothelial cells, suggesting a trans-differentiation of cancer cells into tumor micro-vessels. We demonstrated that this mutation could be used as a predictive biomarker of response to CB-103, a specific NOTCH1-intracellular domain inhibitor. One striking result was the considerable anti-angiogenic effect, coherent with the presence of NOTCH1 mutation in tumor micro-vessels. Conclusions: We identified a frequent, unexpected pL1575P_c4724T_C NOTCH1 mutation as a new biomarker for ccRCC metastases, predictive of response to the CB103 NOTCH1-intracellular domain inhibitor. [ABSTRACT FROM AUTHOR]
- Subjects :
- RENAL cell carcinoma
METASTASIS
ENDOTHELIAL cells
METASTATIC breast cancer
Subjects
Details
- Language :
- English
- ISSN :
- 21623619
- Volume :
- 12
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Experimental Hematology & Oncology
- Publication Type :
- Academic Journal
- Accession number :
- 163724944
- Full Text :
- https://doi.org/10.1186/s40164-023-00408-z