TY - JOUR
T1 - Polo-like kinase 1 inhibition diminishes acquired resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer with T790M mutations
AU - Wang, Yuehong
AU - Singh, Ratnakar
AU - Wang, Liguang
AU - Nilsson, Monique
AU - Goonatilake, Ruchitha
AU - Tong, Pan
AU - Li, Lerong
AU - Giri, Uma
AU - Villalobos, Pamela
AU - Mino, Barbara
AU - Rodriguez-Canales, Jaime
AU - Wistuba, Ignacio
AU - Wang, Jing
AU - Heymach, John V.
AU - Johnson, Faye M.
N1 - Funding Information:
This work was supported by funds from The Lung Cancer Research Foundation (F.M. Johnson), R01 CA 168484 (J.V. Heymach) and generous philanthropic contributions to The University of Texas MD Anderson Cancer Center's Lung Moon Shot Program. Bioinformatics analyses were supported by the National Cancer Institute through M.D. Anderson's Cancer Center Support Grant (P30CA016672). Y. Wang is supported by a research grant from the Zhejiang Provincial Natural Science Foundation of China (LY15H010003).
PY - 2016
Y1 - 2016
N2 - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial-mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.
AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective against non-small cell lung cancer (NSCLC) with activating EGFR mutations, but resistance is inevitable. Mechanisms of acquired resistance include T790M mutations and epithelial-mesenchymal transition (EMT). One potential strategy for overcoming this resistance is the inhibition of polo-like kinase 1 (PLK1) based on our previous studies showing that mesenchymal NSCLC cell lines are more sensitive to PLK1 inhibition than epithelial cell lines. To determine the extent to which PLK1 inhibition overcomes EGFR TKI resistance we measured the effects of the PLK1 inhibitor volasertib alone and in combination with the EGFR inhibitor erlotinib in vitro and in vivo in EGFR mutant NSCLC cell lines with acquired resistance to erlotinib. Two erlotinib-resistant cell lines that underwent EMT had higher sensitivity to volasertib, which caused G2/M arrest and apoptosis, than their parental cells. In all NSCLC cell lines with T790M mutations, volasertib markedly reduced erlotinib resistance. All erlotinib-resistant NSCLC cell lines with T790M mutations had higher sensitivity to erlotinib plus volasertib than to erlotinib alone, and the combination treatment caused G2/M arrest and apoptosis. Compared with either agent alone, the combination treatment also caused significantly more DNA damage and greater reductions in tumor size. Our results suggest that PLK1 inhibition is clinically effective against NSCLC that becomes resistant to EGFR inhibition through EMT or the acquisition of a T790M mutation. These results uncover new functions of PLK1 inhibition in the treatment of NSCLC with acquired resistance to EGFR TKIs.
KW - Drug resistance
KW - Epidermal growth factor receptor
KW - Epithelial-mesenchymal transition
KW - Non-small cell lung cancer
KW - Polo-like kinase
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U2 - 10.18632/oncotarget.10332
DO - 10.18632/oncotarget.10332
M3 - Article
C2 - 27384992
AN - SCOPUS:84982786679
SN - 1949-2553
VL - 7
SP - 47998
EP - 48010
JO - Oncotarget
JF - Oncotarget
IS - 30
ER -