TY - JOUR
T1 - Differential escape mechanisms in cetuximab-resistant head and neck cancer cells
AU - Willey, Christopher D.
AU - Anderson, Joshua C.
AU - Trummell, Hoa Q.
AU - Naji, Faris
AU - de Wijn, Rik
AU - Yang, Eddy S.
AU - Bredel, Markus
AU - Thudi, Nanda K.
AU - Bonner, James A.
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/9/10
Y1 - 2019/9/10
N2 - Acquired cetuximab resistance is a challenge for oncologists treating advanced head and neck carcinoma (HNC). While intrinsic cetuximab resistance mechanism in colorectal cancer is known, resistance in HNC is unclear. We established two different cetuximab resistant HNC cell lines by culturing epidermal growth factor (EGFR) expressing UM–SCC–1 and UM–SCC–6 cell lines in the presence of 5 μg/ml cetuximab. We then explored potential mechanisms of resistance. We found that the 2 cell lines developed resistance by different mechanisms. Specifically, we found that UM–SCC–1 resistant cells (UM–SCC–1R) showed enhanced EGF-induced downstream signals while UM–SCC–6 resistant cells (UM–SCC–6R) demonstrated EGF-independent signaling. Global kinase activity (kinomic) profiling revealed unique signaling differences in the two resistant cell lines. However, both of the resistant lines demonstrated increased phospho-serine 727 and total STAT3 expression compared to the parental lines. STAT3 knockdown promoted increased cytotoxicity both in the presence and absence of cetuximab in the resistant lines suggesting that STAT3 may be a common target in cetuximab resistance.
AB - Acquired cetuximab resistance is a challenge for oncologists treating advanced head and neck carcinoma (HNC). While intrinsic cetuximab resistance mechanism in colorectal cancer is known, resistance in HNC is unclear. We established two different cetuximab resistant HNC cell lines by culturing epidermal growth factor (EGFR) expressing UM–SCC–1 and UM–SCC–6 cell lines in the presence of 5 μg/ml cetuximab. We then explored potential mechanisms of resistance. We found that the 2 cell lines developed resistance by different mechanisms. Specifically, we found that UM–SCC–1 resistant cells (UM–SCC–1R) showed enhanced EGF-induced downstream signals while UM–SCC–6 resistant cells (UM–SCC–6R) demonstrated EGF-independent signaling. Global kinase activity (kinomic) profiling revealed unique signaling differences in the two resistant cell lines. However, both of the resistant lines demonstrated increased phospho-serine 727 and total STAT3 expression compared to the parental lines. STAT3 knockdown promoted increased cytotoxicity both in the presence and absence of cetuximab in the resistant lines suggesting that STAT3 may be a common target in cetuximab resistance.
KW - Cetuximab
KW - Epidermal growth factor receptor
KW - Head and neck cancer
KW - Kinomic profiling
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=85068783116&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068783116&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2019.06.159
DO - 10.1016/j.bbrc.2019.06.159
M3 - Article
C2 - 31311651
AN - SCOPUS:85068783116
SN - 0006-291X
VL - 517
SP - 36
EP - 42
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -
