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Updated: May 9, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Targeted genetic dependency screen facilitates identification of actionable mutations in FGFR4, MAP3K9, and PAK5 in
Shameem Fawdar1, Eleanor W Trotter, Yaoyong Li
1Signalling Networks in Cancer Group, Cancer Research UK, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom.
Abstract:
Approximately 70% of patients with non-small-cell lung cancer present with late-stage disease and have limited treatment options, so there is a pressing need to develop efficacious targeted therapies for these patients. This remains a major challenge as the underlying genetic causes of ~50% of non-small-cell lung cancers remain unknown. Here we demonstrate that a targeted genetic dependency screen is an efficient approach to identify somatic cancer alterations that are functionally important. By using this approach, we have identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5. Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation, suppresses constitutive activation of downstream signaling pathways, and results in specific killing of the lung cancer cells. Genomic profiling of patients with lung cancer is ushering in an era of personalized medicine; however, lack of actionable mutations presents a significant hurdle. Our study indicates that targeted genetic dependency screens will be an effective strategy to elucidate somatic variants that are essential for lung cancer cell viability.
Insights
Targeted genetic screens identified novel kinase mutations (FGFR4, MAP3K9, PAK5) driving non-small-cell lung cancer. Inhibiting these mutated kinases effectively targets cancer cells, offering new therapeutic avenues for patients with limited options.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Non-small-cell lung cancer (NSCLC) often presents at late stages with limited therapeutic options.
- A significant portion of NSCLC cases (~50%) lack identified genetic drivers, hindering targeted therapy development.
- Genomic profiling is advancing personalized medicine, but identifying actionable mutations remains a challenge.
Purpose of the Study:
- To identify functionally important somatic cancer alterations in NSCLC using a targeted genetic dependency screen.
- To discover novel kinase targets for therapeutic intervention in NSCLC.
Main Methods:
- Conducted a targeted genetic dependency screen to identify key somatic alterations in lung cancer.
- Utilized genomic profiling to analyze patient samples.
- Performed targeted depletion of identified mutated kinases.
Main Results:
- Identified gain-of-function mutations in three kinases: FGFR4, MAP3K9, and PAK5.
- These mutations activate the ERK pathway.
- Targeted depletion of mutated kinases inhibited cancer cell proliferation, reduced downstream signaling, and induced specific cancer cell death.
Conclusions:
- Targeted genetic dependency screens are efficient for discovering functionally significant somatic variants in cancer.
- Mutated FGFR4, MAP3K9, and PAK5 represent potential therapeutic targets for NSCLC.
- This approach can help overcome the hurdle of identifying actionable mutations for personalized lung cancer treatment.
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