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| Status |
Public on Apr 30, 2019 |
| Title |
Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Acquired drug resistance to tyrosine kinase inhibitor (TKI) targeted therapies remains a major clinical challenge. In EGFR mutant non-small cell lung cancer (NSCLC), therapeutic failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with resistance to EGFR TKIs in both experimental models and in patients, and may coincide with genetic mechanisms of resistance such as the EGFRT790M gatekeeper mutation. While therapeutic approaches targeting EGFRT790M have been developed, a strategy for overcoming EMT-related resistance remains unclear. We performed whole-genome CRISPR screening on patient-derived, mesenchymal EGFRT790M-positive cell lines and identified FGFR1 as a critical gene promoting resistance to third generation EGFR TKIs. The FGFR1-3 inhibitor, BGJ398 (infigratinib), resensitized resistant mesenchymal-like cell lines to EGFR inhibition in a synergistic manner. Combining EGFR + FGFR inhibitors also inhibited the in vitro survival and expansion of EGFR mutant drug tolerant cells with mesenchymal-like features prior to the development of drug resistance, and delayed the development of in vivo resistance in EGFR mutant NSCLC xenograft tumors. These results suggest that dual EGFR + FGFR blockade may be a promising clinical strategy for preventing and overcoming EMT-associated acquired drug resistance in EGFR mutant NSCLC.
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| Overall design |
PC9, HCC4006, HC1975, HCC827, MGH119 treated for two weeks with vehicle or with 300nM Gefitinib (300nM WZ4002 for H1975). Triplicates (duplicate for PC9 and MGH119)
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| Contributor(s) |
Raoof S, Hata AN, Frisco-Cabanos H, Ji F, Drier Y |
| Citation missing |
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| |
| Submission date |
May 18, 2018 |
| Last update date |
Apr 30, 2019 |
| Contact name |
Sana Raoof |
| E-mail(s) |
sanaraoofmgh@gmail.com
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| Organization name |
Massachusetts General Hospital
|
| Street address |
175 Cambridge St
|
| City |
Boston |
| ZIP/Postal code |
02114 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (30)
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| Relations |
| BioProject |
PRJNA472050 |
| SRA |
SRP148443 |
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