Crosstalk to stromal fibroblasts induces resistance of lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors.
OBJECTIVE
Lung cancers with epidermal growth factor receptor (EGFR)-activating mutations show good clinical response to gefitinib and erlotinib, selective tyrosine kinase inhibitors (TKI) to EGFR, but these tumors invariably develop drug resistance. Host stromal cells have been found to have a considerable effect on the behavior of cancer cells. Little is known, however, about the role of host cells on the sensitivity of cancer cells to receptor TKIs. We have therefore assessed the effect of crosstalk between stromal cells and lung cancer cells harboring EGFR mutations on susceptibility to EGFR-TKIs.


METHODS
We evaluated the gefitinib sensitivity of lung cancer cells with EGFR-activating mutations, PC-9 and HCC827, when cocultured with fibroblasts and coinjected into severe combined immunodeficient mice. We also examined the effect of lung cancer cells to fibroblast recruitment.


RESULTS
Both human fibroblast cell lines and primary cultured fibroblasts produced various levels of hepatocyte growth factor (HGF). Lung cancer cells markedly recruited fibroblasts. The lung cancer cells became resistant to EGFR-TKIs when cocultured in vitro with HGF-producing fibroblasts and coinjected into severe combined immunodeficient mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4, successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo. Colocalization of fibroblasts and HGF was detected in both xenograft tumors in mouse model and lung cancer patient specimens.


CONCLUSIONS
These findings indicate that crosstalk to stromal fibroblasts plays a critical role in lung cancer resistance to EGFR-TKIs and may be an ideal therapeutic target in lung cancer with EGFR-activating mutations.
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.
Wei
W
Wang
Qi
Q
Li
Tadaaki
T
Yamada
Kunio
K
Matsumoto
Isao
I
Matsumoto
Makoto
M
Oda
Go
G
Watanabe
Yoshiyuki
Y
Kayano
Yasuhiko
Y
Nishioka
Saburo
S
Sone
Seiji
S
Yano
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005347:Fibroblasts / Q000378:metabolism*; D000077156:Gefitinib; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D020239:Receptor Cross-Talk; D017154:Stromal Cells / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D000077156:Gefitinib