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The Differential Effect of TGFβ Stimulation on Erlotinib‐Resistant and ‐Sensitive NSCLC
Author(s) -
Krentz Madeline,
Blankenship Bradley,
Black Esther
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.884.16
Subject(s) - erlotinib , epithelial–mesenchymal transition , a549 cell , cancer research , egfr inhibitors , chemistry , transforming growth factor , biology , medicine , cell , epidermal growth factor receptor , metastasis , cancer , biochemistry
Background TGFβ functions as a tumor suppressor in early tumors, but shifts to pro‐metastatic activity in later stages by inducing epithelial‐to‐mesenchymal transition (EMT). Others have shown that Non‐Small Cell Lung Cancers (NSCLC) that have undergone EMT are resistant to EGFR inhibition. We hypothesize that TGFβ promotes a specific gene expression program and an EMT phenotype resulting in erlotinib‐resistant NSCLC. Methods. To test if TGFβ influences erlotinib‐resistance in NSCLC, we exposed NSCLC cells to extended TGFβ treatment in the presence and absence of TGFβRII inhibitor, SB‐431542. Changes in morphology were assessed by microscopy. TGFβ canonical and non‐canonical signaling effectors/EMT marker protein expression were quantified by western blot and immunofluorescence after TGFβ treatment. Treatment‐induced motility was assessed by Transwell assay and response to erlotinib tested. Results. TGFβ induces mesenchymal morphology in erlotinib‐resistant, A549 cells. TGFβ inhibition generates an EMT‐intermediate phenotype in erlotinib‐sensitive, PC9 cells. TGFβ activates different downstream signaling programs and EMT marker expression reflects morphology changes in each cell line. TGFβ increases mobility in A549 while its inhibition increases mobility in PC9. Erlotinib sensitivity was unchanged in A549 while PC9 showed increased erlotinib resistance following TGFβ inhibition, perhaps due to EGFR siganls. Conclusion TGFβ induces a mesenchymal morphology in A549 consistent with pro‐metastatic, TGFβ function seen in erlotinib‐resistant NSCLC. PC9 develop an EMT‐intermediate phenotype following TGFβ blockade, suggesting that its inhibition promotes EMT initiation but not a complete transition. College monies funded this work.