Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer.

Oncogene 2019 09 19;38(37):6399-6413. Epub 2019 Jul 19.

Massachusetts General Hospital (MGH) Cancer Center, Charlestown, MA, USA.

Evolved resistance to tyrosine kinase inhibitor (TKI)-targeted therapies remains a major clinical challenge. In epidermal growth factor receptor (EGFR) mutant non-small-cell lung cancer (NSCLC), failure of EGFR TKIs can result from both genetic and epigenetic mechanisms of acquired drug resistance. Widespread reports of histologic and gene expression changes consistent with an epithelial-to-mesenchymal transition (EMT) have been associated with initially surviving drug-tolerant persister cells, which can seed bona fide genetic mechanisms of resistance to EGFR TKIs. While therapeutic approaches targeting fully resistant cells, such as those harboring an EGFR mutation, have been developed, a clinical strategy for preventing the emergence of persister cells remains elusive. Using mesenchymal cell lines derived from biopsies of patients who progressed on EGFR TKI as surrogates for persister populations, we performed whole-genome CRISPR screening and identified fibroblast growth factor receptor 1 (FGFR1) as the top target promoting survival of mesenchymal EGFR mutant cancers. Although numerous previous reports of FGFR signaling contributing to EGFR TKI resistance in vitro exist, the data have not yet been sufficiently compelling to instigate a clinical trial testing this hypothesis, nor has the role of FGFR in promoting the survival of persister cells been elucidated. In this study, we find that combining EGFR and FGFR inhibitors inhibited the survival and expansion of EGFR mutant drug-tolerant cells over long time periods, preventing the development of fully resistant cancers in multiple vitro models and in vivo. These results suggest that dual EGFR and FGFR blockade may be a promising clinical strategy for both preventing and overcoming EMT-associated acquired drug resistance and provide motivation for the clinical study of combined EGFR and FGFR inhibition in EGFR-mutated NSCLCs.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-019-0887-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742540PMC
September 2019
12 Reads

Publication Analysis

Top Keywords

egfr mutant
16
egfr
12
egfr fgfr
12
persister cells
12
factor receptor
8
fully resistant
8
growth factor
8
drug resistance
8
acquired drug
8
egfr tkis
8
lung cancer
8
clinical strategy
8
egfr tki
8
promoting survival
8
strategy preventing
8
resistance egfr
8
resistance
6
fgfr
5
cells
5
clinical
5

References

(Supplied by CrossRef)

TJ Lynch et al.
N Engl J Med 2004

JG Paez et al.
Science 2004

TS Mok et al.
N Engl J Med 2009

M Maemondo et al.
N Engl J Med 2010

S Kobayashi et al.
N Engl J Med 2005

W Pao et al.
PLoS Med 2005

JA Engelman et al.
Science 2007

LV Sequist et al.
Sci Transl Med 2011

K Azuma et al.
Oncotarget 2014

AS Crystal et al.
Science 2014

H Terai et al.
Mol Cancer Res 2013

Similar Publications