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Cancer Genomics and Diagnostics / Renal Cell Carcinoma Treatment · Journal article
Genes · July 12, 2026
Encouraging direction, but not yet definitive.
A kinome-wide CRISPR/Cas9 screen in RCC cells identified MEK1 as a synthetic lethal target with cabozantinib. Combining the MEK inhibitor cobimetinib with cabozantinib showed synergistic effects in two RCC cell lines and suppressed tumor growth in vivo, suggesting potential to overcome cabozantinib resistance, but clinical validation is needed.
Kinome-wide CRISPR/Cas9 synthetic lethal screen with cell viability and xenograft validation. 786-o and A498 renal cell carcinoma cell lines; xenograft models derived from RCC cells.. Intervention: Cobimetinib (MEK inhibitor) combined with cabozantinib (tyrosine kinase inhibitor).. Compared with: Vehicle control; cabozantinib or cobimetinib alone..
CRISPR/Cas9 screening identified four candidate genes (MEK1, DCLK1, DYRK3, FGFR1) for synthetic lethality with cabozantinib in RCC cells. Cobimetinib plus cabozantinib exhibited synergistic effect in cell proliferation assays using 786-o and A498 RCC cells. Xenograft assay revealed significant synergistic effect of cobimetinib and cabozantinib in vivo.
Long-term toxicity, optimal dosing, and patient subgroup analysis are not addressed.
The identified cobimetinib–cabozantinib combination uses two existing FDA-approved drugs and may address cabozantinib resistance in RCC; however, clinical trials are required to validate efficacy, safety, and patient selection in human disease.
Preclinical discovery of a synergistic drug combination in RCC cells and xenografts, supported by mechanistic CRISPR screening and validated in two cell lines, but lacking human clinical evidence and requiring translation to the clinic.
As stated by the source record.
Quoted from the source exactly as published.
The identified cobimetinib–cabozantinib combination uses two existing FDA-approved drugs and may address cabozantinib resistance in RCC; however, clinical trials are required to validate efficacy, safety, and patient selection in human disease.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Background/Objectives: Cabozantinib is a tyrosine kinase inhibitor that primarily targets MET. It has become an important drug in the treatment of renal cell carcinoma (RCC); however, many patients do not respond to cabozantinib treatment and there is no effective next-line therapy. In this study, we identified molecular-targeted drugs that exhibit synergistic effects with cabozantinib using CRISPR/Cas9 screening. Methods: A kinome-wide synthetic lethal CRISPR/Cas9 screen was used to identify target molecules using 786-o RCC cells. A library was generated, and treatment with vehicle or cabozantinib was carried out, followed by next-generation sequencing to identify candidate genes. A combination index based on the Chou–Talalay method was used to evaluate the synergistic effect of cabozantinib through cell viability assays. Xenograft assays were conducted to determine the effect in vivo. Results: CRISPR/Cas9-based screening revealed four genes (MEK1, DCLK1, DYRK3, and FGFR1) that were candidates for synthetic lethality by cabozantinib in RCC cells. We focused on MEK1 because the MEK1 inhibitor cobimetinib has been approved for melanoma treatment. In a cell proliferation assay using 786-o and A498 RCC cells, the combination of cobimetinib and cabozantinib exhibited a synergistic effect. A xenograft assay also revealed a significant synergistic effect of cobimetinib and cabozantinib. Conclusions: CRISPR/Cas9 screening identified MEK1 as a candidate for a synthetic lethal target with cabozantinib in RCC. The combined inhibition of MET/VEGFR and MEK1 suppressed compensatory MAPK reactivation and downregulated the PI3K-Akt pathway, including the survival-associated genes PPP2R3B and ATF6B, and produced significant tumor growth suppression in vivo. These findings highlight the potential of cabozantinib plus cobimetinib, an already-FDA-approved MEK inhibitor, as a readily translatable combination strategy to overcome cabozantinib resistance in RCC.
Taken from the source record, never inferred. Follow any of these and new work involving them reaches your briefing.