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Inhibitor-sensitive FGFR1 amplification in human non-small cell lung cancer
Amit Dutt1, Alex H Ramos, Peter S Hammerman
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. adutt@actrec.gov.in
Background:
Squamous cell lung carcinomas account for approximately 25% of new lung carcinoma cases and 40,000 deaths per year in the United States. Although there are multiple genomically targeted therapies for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma.
Methodology/Principal Findings:
Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes-WHSC1L1, LETM2, and FGFR1-is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas. Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition.
Conclusions/Significance:
These studies show that FGFR1 amplification is common in squamous cell lung cancer, and that FGFR1 may represent a promising therapeutic target in non-small cell lung cancer.
Insights
Fibroblast growth factor receptor 1 (FGFR1) amplification is common in squamous cell lung cancer. This finding suggests FGFR1 may be a potential therapeutic target for non-small cell lung cancer patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Squamous cell lung carcinoma (SqCLC) represents 25% of lung cancer cases in the US, causing 40,000 deaths annually.
- Unlike lung adenocarcinoma, SqCLC currently lacks genomically targeted therapies.
- There is a critical unmet need for novel therapeutic strategies in SqCLC.
Purpose of the Study:
- To investigate potential therapeutic targets in squamous cell lung carcinoma.
- To identify genetic alterations common in SqCLC.
- To evaluate the role of FGFR1 in non-small cell lung cancer (NSCLC) growth.
Main Methods:
- Single nucleotide polymorphism (SNP) array analysis was employed to identify chromosomal amplifications.
- A NSCLC cell line with focal FGFR1 amplification was utilized.
- FGFR1 activity was inhibited using FGFR1-specific shRNAs and small molecule enzymatic inhibitors.
Main Results:
- Amplification of the 8p11-12 chromosomal region, including FGFR1, was identified in 21% of SqCLC cases and 3% of lung adenocarcinomas.
- The NSCLC cell line with FGFR1 amplification demonstrated dependency on FGFR1 for cell growth.
- Inhibition of FGFR1 activity led to significant cell growth inhibition in vitro.
Conclusions:
- FGFR1 amplification is a frequent event in squamous cell lung cancer.
- FGFR1 activity is crucial for the proliferation of FGFR1-amplified NSCLC cells.
- FGFR1 represents a promising therapeutic target for a subset of NSCLC patients.
