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Updated: May 13, 2026
Genetic Profiling and Genome-Scale Dropout Screening to Identify Therapeutic Targets in Mouse Models of Malignant Peripheral Nerve Sheath Tumor
Published on: August 25, 2023
Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer
Sanne R Martens-de Kemp1, Remco Nagel, Marijke Stigter-van Walsum
1AuDepartment of Otolaryngology/Head-Neck Surgery, VU University Medical Center, Amsterdam, the Netherlands.
Purpose:
Despite continuous improvement of treatment regimes, the mortality rates for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) remain disappointingly high and novel anticancer agents are urgently awaited.
Experimental Design:
We combined the data from genome-wide siRNA screens on tumor cell lethality in a lung and a head and neck cancer cell line.
Results:
We identified 71 target genes that seem essential for the survival of both cancer types. We identified a cluster of 20 genes that play an important role during G2-M phase transition, underlining the importance of this cell-cycle checkpoint for tumor cell survival. Five genes from this cluster (CKAP5, KPNB1, RAN, TPX2, and KIF11) were evaluated in more detail and have been shown to be essential for tumor cell survival in both tumor types, but most particularly in HNSCC. Phenotypes that were observed following siRNA-mediated knockdown of KIF11 (kinesin family member 11) were reproduced by inhibition of KIF11 using the small-molecule inhibitor ispinesib (SB-715992). We showed that ispinesib induces a G2 arrest, causes aberrant chromosome segregation, and induces cell death in HNSCC in vitro, whereas primary keratinocytes are less sensitive. Furthermore, growth of HNSCC cells engrafted in immunodeficient mice was significantly inhibited after ispinesib treatment.
Conclusion:
This study identified a wide array of druggable genes for both lung and head and neck cancer. In particular, multiple genes involved in the G2-M checkpoint were shown to be essential for tumor cell survival, indicating their potential as anticancer targets.
Insights
Researchers identified essential genes for non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) survival. Targeting the G2-M cell cycle checkpoint, particularly KIF11 with ispinesib, shows promise for new anticancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) have high mortality rates despite treatment advances.
- Novel therapeutic strategies are urgently needed for these aggressive cancers.
Purpose of the Study:
- To identify novel drug targets essential for the survival of both NSCLC and HNSCC.
- To investigate the role of cell-cycle regulation in tumor cell survival.
Main Methods:
- Genome-wide siRNA screens were performed on lung and head and neck cancer cell lines to identify lethal genes.
- Key genes, including CKAP5, KPNB1, RAN, TPX2, and KIF11, were further analyzed.
- The efficacy of KIF11 inhibition using ispinesib was evaluated in vitro and in vivo.
Main Results:
- 71 genes essential for the survival of both cancer types were identified.
- A cluster of 20 genes involved in G2-M phase transition was highlighted.
- Ispinesib treatment induced G2 arrest, aberrant chromosome segregation, and cell death in HNSCC, with significant tumor growth inhibition in vivo.
Conclusions:
- This study identified numerous druggable targets for NSCLC and HNSCC.
- Genes regulating the G2-M checkpoint are critical for tumor cell survival and represent promising anticancer targets.
- KIF11 inhibition via ispinesib demonstrates therapeutic potential against HNSCC.
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