scholarly journals Cetuximab-modified mesoporous silica nano-medicine specifically targets EGFR-mutant lung cancer and overcomes drug resistance

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yuetong Wang ◽  
Hsin-Yi Huang ◽  
Liu Yang ◽  
Zhanxia Zhang ◽  
Hongbin Ji
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Mesoporous Silica ◽  
Egfr Mutant ◽  
Nano Medicine

scholarly journals Inhibition of Casein Kinase 1 Alpha Prevents Acquired Drug Resistance to Erlotinib in EGFR-Mutant Non–Small Cell Lung Cancer

2015 ◽  
Vol 75 (22) ◽  
pp. 4937-4948 ◽  
Author(s):  
Alexandra B. Lantermann ◽  
Dongshu Chen ◽  
Kaitlin McCutcheon ◽  
Greg Hoffman ◽  
Elizabeth Frias ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Casein Kinase 1 ◽  
Acquired Drug Resistance ◽  
Egfr Mutant ◽  
Casein Kinase 1 Alpha

scholarly journals Branched-Chain Amino Acid Metabolic Reprogramming Orchestrates Drug Resistance to EGFR Tyrosine Kinase Inhibitors

2019 ◽  
Author(s):  
Yuetong Wang ◽  
Jian Zhang ◽  
Shengxiang Ren ◽  
Dan Sun ◽  
Hsin-Yi Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Metabolic Reprogramming ◽  
Tki Resistance ◽  
Combinational Treatment ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Tki

SUMMARYDrug resistance is a significant hindrance to effective cancer treatment. Although resistance mechanisms of epidermal growth factor receptor (EGFR)-mutant cancer cells to lethal EGFR tyrosine kinase inhibitors (TKI) treatment have been investigated intensively, how cancer cells orchestrate adaptive response under sublethal drug challenge remains largely unknown. Here we find that 2-hour sublethal TKI treatment elicits a transient drug-tolerant state in EGFR-mutant lung cancer cells. Continuous sublethal treatment reinforces this tolerance and eventually establishes long-term TKI resistance. This adaptive process involves H3K9 demethylation-mediated epigenetic upregulation of branched-chain amino acid aminotransferase 1 (BCAT1) and subsequent metabolic reprogramming, which promotes TKI resistance through attenuating reactive oxygen species (ROS) accumulation. Combinational treatment with TKI and ROS-inducing reagents overcomes this drug resistance in preclinical mouse models. Clinical information analyses support the correlation of BCAT1 expression with EGFR TKI response. Collectively, our findings reveal the importance of epigenetically regulated BCAT1-engaged metabolism reprogramming in TKI resistance in lung cancer.HIGHLIGHTSSublethal EGFR TKI treatment induces transient drug-tolerant state and long-term resistance in EGFR-mutant lung cancer cellsEpigenetically regulated BCAT1-mediated metabolic reprogramming orchestrates EGFR TKI-induced drug resistanceCombinational treatment with TKI and ROS-inducing agents overcomes the drug resistance induced by EGFR TKI treatment

scholarly journals Autophagy determines osimertinib resistance through regulation of stem cell-like properties in EGFR-mutant lung cancer

2018 ◽  
Author(s):  
Li Li ◽  
Yubo Wang ◽  
Lin Jiao ◽  
Caiyu Lin ◽  
Conghua Lu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Stem Cell ◽  
Lung Cancer Patients ◽  
Knock Down ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Autophagy Inhibition ◽  
Resistant Cells

ABSTRACTDrug resistance to Osimertinib, a 3rd-generation EGFR-TKI is inevitable. Autophagy plays a contradictory role in resistance of 1stand 2ndgeneration EGFR-TKI, and its significance in osimertinib resistance is much less clear. We therefore investigated whether autophagy determines osimertinib resistance. First, osimertinib induced autophagy to a much greater extent than that of gefitinib, and autophagy inhibition further increased osimertinib efficacy. Next, enhanced autophagy was found in osimertinib resistant cells and autophagy inhibition partially reversed osimertinib resistance. Enhanced stem-cell like properties were found in resistant cells, and siRNA-knock down ofSOX2orALDH1A1reversed osimertinib resistance. Of note, autophagy inhibition or siRNA-knock down of Beclin-1 decreased expression of SOX2 and ALDH1A1 and stem-cell like properties. Next, autophagy inhibition and osimertinib in combination effectively blocked tumor growth in xenografts, which was associated with decreased autophagy and stem cell-like propertiesin vivo. Finally, enhanced autophagy was found in lung cancer patients with resistance to osimertinib. In conclusion, the current study delineates a previously unknown function of autophagy in determining osimertinib resistance through promoting stem-cell like properties.

scholarly journals Tumor regression mediated by oncogene withdrawal or erlotinib stimulates infiltration of inflammatory immune cells in EGFR mutant lung tumors

2018 ◽  
Author(s):  
Deborah Ayeni ◽  
Braden Miller ◽  
Alexandra Kuhlman ◽  
Ping-Chih Ho ◽  
Camila Robles-Oteiza ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Immune Cells ◽  
Kinase Inhibitors ◽  
Tumor Regression ◽  
Growth Factor Receptor ◽  
Lung Tumors ◽  
Combination Strategies ◽  
Before And After ◽  
Egfr Mutant

AbstractEpidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) like erlotinib are effective for treating patients with EGFR mutant lung cancer; however, drug resistance inevitably emerges. Approaches to combine immunotherapies and targeted therapies to overcome or delay drug resistance have been hindered by limited knowledge of the effect of erlotinib on tumor-infiltrating immune cells. Using mouse models, we studied the immunological profile of mutantEGFR-driven lung tumors before and after erlotinib treatment. We found that erlotinib triggered the recruitment of inflammatory T cells into the lungs. Interestingly, this phenotype could be recapitulated by tumor regression mediated by deprivation of the EGFR oncogene indicating that tumor regression alone was sufficient for these immunostimulatory effects. Erlotinib treatment also led to increased maturation of myeloid cells and an increase in CD40+ dendritic cells. Our findings lay the foundation for understanding the effects of TKIs on the tumor microenvironment and highlights potential avenues for investigation of targeted and immuno-therapy combination strategies to treat EGFR mutant lung cancer.

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