_:b531233972 "5"^^ . . _:b531234001 . . _:b531233975 "4"^^ . _:b531234000 . _:b531234051 . _:b531233974 . _:b531233974 "4"^^ . . . . _:b531234003 . . _:b531234002 . _:b531233969 "5"^^ . _:b531233968 "5"^^ . . _:b531234013 . . _:b531233971 "5"^^ . . _:b531234012 . _:b531233970 "5"^^ . _:b531234015 . _:b531233981 "3"^^ . . _:b531234014 . _:b531234015 . . . _:b531233980 "3"^^ . _:b531234009 . _:b531233983 "3"^^ . _:b531234105 . _:b531234008 . _:b531233986 . _:b531233982 "3"^^ . . _:b531234011 . _:b24815010 "implication in the EMT phenomenon, EMT transcriptional drivers (e.g., SNAIL factors) can also regulate other cellular processes related to cell proliferation and survival, thus contributing to resistance to pro-apoptotic stresses>>363738<<39. Accordingly, we recently revealed that a significant reduction in tumor growth and dramatic gain in sensitivity to the growth-inhibitory effects of the anti-HER2 monoclonal antibody trastuzumab in vivo can be observed upon injection of" . _:b531233977 "4"^^ . _:b24815023 "loss of biomarkers associated with epithelial status and gain of biomarkers associated with mesenchymal status. A microRNA gene expression signature targeting EMT has been recently shown to predict response to erlotinib45. Byers et al.>>46<< recently developed a robust EMT signature that highlights different drug responsiveness patterns for epithelial and mesenchymal NSCLC cells and can predict resistance to EGFR TKIs regardless of EGFR mutation status." . _:b531234028 . _:b531234037 . _:b531234010 . _:b531233976 "4"^^ . . _:b531234021 . _:b531234088 . _:b531234039 . _:b531233979 "4"^^ . _:b531234020 . _:b531234042 . _:b531233978 "4"^^ . . _:b531234023 . _:b24815015 "mutation in EGFR exon 19, Suda et al.29 established that mesenchymal status, not a specific oncogenic-activated protein, could sufficiently promote loss of EGFR dependence to confer resistance to erlotinib. More recently, Chang et al.>>42<< confirmed that in the absence of the common second-site EGFR mutation T790M or MET amplification, acquired resistance to gefitinib occurs in EGFR-mutated PC9 cells that have undergone EMT." . _:b531233989 "3"^^ . _:b531234022 . . _:b24815024 . _:b531233988 "3"^^ . _:b531234017 . _:b531233991 "3"^^ . _:b531234055 . _:b531234016 . _:b531233990 "3"^^ . . _:b531234019 . _:b531233985 "3"^^ . . _:b531234018 . . _:b531234094 . _:b531233984 "3"^^ . _:b531234029 . _:b24815031 . _:b531233987 "3"^^ . _:b531234028 . _:b24815021 "Earlier studies have suggested an active involvement of EMT in resistance to EGFR TKIs25274344, and accordingly, E-cadherin expression has been reported to operate as a biomarker capable of predicting the clinical efficacy of gefitinib>>27<<. However, it should be noted that these studies were largely based on NSCLC cells expressing wild-type EGFR; therefore, these studies did not mimic clinical usage of EGFR TKIs because EGFR wild-type NSCLC cells are intrinsically resistant" . _:b531233986 "3"^^ . _:b531234031 . _:b531233997 "3"^^ . _:b531234030 . _:b531234102 . _:b24815012 . _:b531233996 "3"^^ . _:b531233983 . _:b531234025 . _:b531233999 "3"^^ . _:b531234021 . . _:b531234024 . _:b531234043 . _:b531233998 "3"^^ . _:b531234027 . _:b24815037 "During the preparation of this manuscript, Shien et al.>>59<< reported that acquired resistance to the EGFR inhibitor gefitinib was associated with a manifestation of stem cell-like properties in EGFR-mutated NSCLC cells, including EMT features, overexpression of the stem cell-marker aldehyde" . _:b531233993 "3"^^ . _:b531234026 . . _:b531233992 "3"^^ . _:b531234037 . _:b531233995 "3"^^ . . _:b531234036 . _:b531234104 . _:b531233994 "3"^^ . _:b531234039 . . _:b531234005 "2"^^ . _:b531234029 . . _:b531234038 . _:b531234004 "2"^^ . . _:b531234086 . . _:b531234033 . _:b531234007 "2"^^ . . _:b531234045 . _:b531234003 . _:b531234032 . _:b531234006 "2"^^ . . _:b531234035 . _:b531234001 "2"^^ . _:b531234034 . _:b531234050 . . _:b531234000 "2"^^ . _:b531234045 . _:b531234003 "2"^^ . _:b531234092 . _:b531234044 . _:b531234002 "2"^^ . . . _:b531234047 . _:b531234013 "2"^^ . _:b24815032 "Silibinin appears to operate as a potent natural agent leading to the reversal of EMT by decreasing the levels of key EMT TFs (e.g., SLUG) and increasing the expression levels of E-cadherin>>525354<<. Silibinin has been shown to reduce IGF-1R phosphorylation, indicating an inhibitory effect on the IGF-1R-mediated signaling pathway in cancer cells5556. Through using a milk thistle extract rich in silybin meglumine, a commercially used" . "PMC0" . _:b531234046 . _:b531234012 "2"^^ . _:b531234041 . _:b531234015 "2"^^ . _:b531234112 . . _:b531234040 . _:b531234020 . _:b531234014 "2"^^ . _:b531234021 . _:b24815008 . _:b531234022 . _:b531234023 . _:b24815004 . _:b531234043 . _:b531234016 . _:b531234009 "2"^^ . _:b531234017 . _:b531234018 . _:b531234019 . _:b24815005 . . _:b531233977 . _:b531234042 . _:b531234028 . _:b531234008 "2"^^ . _:b531234029 . _:b531234030 . _:b531234091 . _:b531234031 . _:b24815006 . _:b531234024 . _:b531234011 "2"^^ . _:b531234025 . _:b531234026 . . _:b531234063 . _:b531234027 . _:b24815007 . _:b531233991 . _:b531234010 "2"^^ . _:b531234036 . _:b531234037 . _:b24815013 "Using erlotinib hyper-resistant cells established from H1650 cells, which are EGFR mutant but unresponsive to erlotinib due to PTEN deletion, Yao et al>>41<< were pioneers at uncovering the existence of a TGF\u03B2-driven subpopulation of NSCLC cells intrinsically resistant to erlotinib that display features suggestive of EMT." . . . _:b531234038 . _:b531234039 . _:b531234032 . _:b24815000 . _:b531234021 "2"^^ . _:b531234033 . _:b531234034 . _:b531234035 . _:b24815038 "While the majority of previously reported cells that acquired resistance to the EGFR TKIs gefitinib and erlotinib were established with stepwise escalation of the EGFR TKI concentration, when Shien et al.>>59<< established gefitinib-resistant cells with both the stepwise escalation method and the high-concentration exposure method, they observed that the manner of exposure to the EGFR TKI notable influenced the mechanism of acquired resistance;" . _:b24815001 . _:b531234044 . _:b531234020 "2"^^ . _:b531234045 . _:b531234046 . _:b24815024 "that a \u201Cmesenchymal transition signature\u201D likely reflects a reversible process in which the mesenchymal markers may dynamically appear and disappear depending on intrinsic (i.e., cell autonomous) and/or microenvironmental signals>>41<<. Consequently, the potential use of EMT-like predictive signatures would have high selectively but not might have the sensitivity to predict acquired resistance to erlotinib." . _:b531234047 . _:b24815002 . _:b531234040 . _:b531234023 "2"^^ . _:b531234041 . _:b531234042 . . _:b24815003 . _:b531234043 . _:b531233988 . _:b531234022 "2"^^ . _:b531233989 . _:b531234059 . _:b531233990 . _:b531233997 . _:b531233991 . _:b24815012 . _:b531233984 . _:b531234017 "2"^^ . _:b531233985 . _:b531234044 . _:b531233986 . _:b531233987 . _:b24815013 . _:b531233996 . _:b531234016 "2"^^ . _:b531233997 . _:b531233998 . _:b531233999 . _:b24815014 . . _:b531233992 . _:b531234019 "2"^^ . _:b531233993 . _:b531233994 . . _:b24815015 . _:b531233995 . _:b531234004 . _:b531234018 "2"^^ . _:b531234005 . . . _:b531234006 . _:b531234007 . _:b24815008 . _:b531234000 . _:b531234029 "2"^^ . _:b531234001 . _:b531234002 . _:b531234003 . _:b24815009 . _:b531234012 . _:b531234028 "2"^^ . _:b531234013 . _:b531234014 . _:b24815031 "Silibinin appears to operate as a potent natural agent leading to the reversal of EMT by decreasing the levels of key EMT TFs (e.g., SLUG) and increasing the expression levels of E-cadherin>>5253<<54. Silibinin has been shown to reduce IGF-1R phosphorylation, indicating an inhibitory effect on the IGF-1R-mediated signaling pathway in cancer cells5556. Through using a milk thistle extract rich in silybin meglumine, a commercially" . . _:b531234015 . _:b24815010 . _:b531234008 . _:b531234031 "2"^^ . _:b531234009 . _:b531234010 . _:b531234011 . _:b24815011 . _:b531234098 . _:b531234084 . _:b531234030 "2"^^ . _:b24815020 . _:b531233993 . _:b531234025 "2"^^ . _:b24815021 . _:b531233964 . _:b531234024 "2"^^ . _:b531233965 . _:b24815010 . _:b531233966 . _:b531233967 . _:b24815022 . _:b531234027 "2"^^ . _:b531233962 . . _:b531233963 . _:b24815023 . _:b531233972 . _:b531234026 "2"^^ . _:b531233973 . _:b531233974 . _:b531233975 . _:b24815016 . _:b531233968 . _:b531234095 . _:b531234037 "2"^^ . _:b531233969 . _:b531233970 . . _:b531233971 . _:b24815017 . . _:b531233980 . _:b531234036 "2"^^ . _:b531233981 . _:b531233982 . _:b531233983 . _:b24815018 . . _:b531233976 . _:b531234039 "2"^^ . _:b531233977 . _:b531233978 . _:b531233979 . _:b24815021 . _:b24815019 . _:b531234038 "2"^^ . . _:b531233967 . _:b24815028 . _:b531234033 "2"^^ . _:b24815029 . _:b531234032 "2"^^ . _:b24815035 . _:b531234054 . _:b531233966 . _:b24815030 . _:b531234035 "2"^^ . _:b24815031 . _:b531234034 "2"^^ . _:b24815018 . _:b24815024 . _:b531234045 "2"^^ . . _:b24815025 . _:b531233969 . _:b531234044 "2"^^ . _:b24815029 "the active constituent of silymarin isolated from the dried fruits of milk thistle (Silybum marianum) plant47484950, to EGFR TKIs drastically suppresses tumor growth in primary and acquired-resistance cells with the EGFR T790M mutation>>51<< may open a new therapeutic avenue to clinically manage EMT-driven acquired resistance to erlotinib." . . _:b24815026 . _:b531234047 "2"^^ . . _:b24815027 . _:b531234046 "2"^^ . _:b24815036 . _:b531234041 "2"^^ . . _:b24815037 . _:b531234040 "2"^^ . _:b24815038 . . _:b531234043 "2"^^ . . _:b24815003 "that clinical trials of IGF-1R inhibitors with demonstrated activity in unselected NSCLC patients might play a role in association with EGFR inhibitors in the management of NSCLCs with acquired resistance to gefitinib/erlotinib>>3233<<. It should be noted that increased IGF-1R activation in erlotinib-refractory delE746-A750-mutated PC-9 cells occurred in our lab models independently of changes in IGF-binding proteins (IGFBPs) (data not shown)." . . . _:b531234042 "2"^^ . _:b531234060 . _:b531234103 . . _:b24815032 . _:b531234053 "2"^^ . . . _:b531233979 . _:b24815033 . . _:b531234052 "2"^^ . _:b24815034 . _:b531234055 "2"^^ . _:b24815000 "discussion" . _:b531234022 . _:b24815035 . . _:b531233971 . _:b531234054 "2"^^ . _:b24815033 . _:b531234041 . _:b531234049 "2"^^ . _:b531234046 . _:b531234048 "2"^^ . . _:b531234051 "2"^^ . _:b531233985 . _:b531234050 "2"^^ . . _:b531234061 "2"^^ . _:b24815007 . . _:b531234060 "2"^^ . . _:b531234070 . _:b531234063 "2"^^ . _:b531234093 . _:b531234062 "2"^^ . _:b531234057 "2"^^ . _:b531234056 "2"^^ . . _:b531234059 "2"^^ . . _:b531234058 "2"^^ . _:b24815037 . . _:b531234087 . . _:b531234069 "2"^^ . . _:b531234068 "2"^^ . _:b531234071 "2"^^ . _:b24815038 . _:b24815027 "In this regard, it is worth noting that a landmark study showing that the addition of silibinin, which is the active constituent of silymarin isolated from the dried fruits of milk thistle (Silybum marianum) plant>>474849<<50, to EGFR TKIs drastically suppresses tumor growth in primary and acquired-resistance cells with the EGFR T790M mutation51 may open a new therapeutic avenue to clinically manage EMT-driven acquired resistance to erlotinib." . _:b531234090 . . _:b531234070 "2"^^ . _:b531234065 "2"^^ . _:b531234071 . _:b531234064 "2"^^ . . _:b531234081 . . _:b531234074 . _:b531234007 . _:b531234067 "2"^^ . _:b531234066 "2"^^ . . _:b24815009 "implication in the EMT phenomenon, EMT transcriptional drivers (e.g., SNAIL factors) can also regulate other cellular processes related to cell proliferation and survival, thus contributing to resistance to pro-apoptotic stresses>>3637<<3839. Accordingly, we recently revealed that a significant reduction in tumor growth and dramatic gain in sensitivity to the growth-inhibitory effects of the anti-HER2 monoclonal antibody trastuzumab in vivo can be observed upon injection" . _:b24815018 "Earlier studies have suggested an active involvement of EMT in resistance to EGFR TKIs>>2527<<4344, and accordingly, E-cadherin expression has been reported to operate as a biomarker capable of predicting the clinical efficacy of gefitinib27." . _:b531234077 "2"^^ . _:b531234076 "2"^^ . _:b531234079 "2"^^ . _:b531234058 . _:b531234078 "2"^^ . _:b531234032 . _:b531234073 "2"^^ . _:b531234072 "2"^^ . . _:b531234001 . _:b531234075 "2"^^ . _:b531234074 "2"^^ . _:b531234085 "2"^^ . _:b531234035 . _:b24815004 . _:b531234084 "2"^^ . _:b531234004 . _:b531234087 "2"^^ . _:b24815032 . _:b531234086 "2"^^ . _:b531234081 "2"^^ . _:b531234080 "2"^^ . _:b531234083 "2"^^ . _:b531234020 . _:b531234082 "2"^^ . . _:b531234076 . _:b531234093 "2"^^ . . _:b531234092 "2"^^ . . _:b531234095 "2"^^ . _:b531234094 "2"^^ . _:b24815028 "In this regard, it is worth noting that a landmark study showing that the addition of silibinin, which is the active constituent of silymarin isolated from the dried fruits of milk thistle (Silybum marianum) plant>>47484950<<, to EGFR TKIs drastically suppresses tumor growth in primary and acquired-resistance cells with the EGFR T790M mutation51 may open a new therapeutic avenue to clinically manage EMT-driven acquired resistance to erlotinib." . . _:b531234089 "2"^^ . _:b531234053 . _:b531234018 . _:b531234088 "2"^^ . _:b531234052 . . _:b531234091 "2"^^ . _:b531234055 . _:b531234067 . . _:b24815029 . . _:b531234090 "2"^^ . _:b531234054 . _:b531234101 "2"^^ . _:b531234049 . _:b531234100 "2"^^ . _:b531234048 . _:b531234103 "2"^^ . _:b531234051 . . _:b531234036 . _:b531234102 "2"^^ . _:b531234050 . _:b531234097 "2"^^ . _:b531234061 . _:b531234109 . _:b24815004 "Whereas earlier studies have demonstrated that a loss of IGFBP (IGFBP-3 and IGFBP-4) expression levels in tumor cells treated with EGFR TKIs activated IGF-1R signaling, which in turn mediated resistance to an EGFR antagonist>>20<<31, our analyses failed to detect significant changes in the secretion levels of IGFBPs in delE746-A750-mutated PC-9 cells with acquired resistance to erlotinib." . _:b531234096 "2"^^ . _:b531234060 . . _:b531234099 "2"^^ . _:b531234063 . _:b531234057 . . _:b531234098 "2"^^ . _:b531234062 . _:b531234109 "2"^^ . _:b24815000 . _:b531234057 . _:b531234108 "2"^^ . _:b531234056 . _:b531234053 . . _:b531234111 "2"^^ . _:b531234059 . _:b531233987 . _:b531234110 "2"^^ . _:b531234058 . _:b531234013 . _:b531234105 "2"^^ . _:b531234069 . . _:b531234083 . _:b531234104 "2"^^ . _:b531234068 . _:b531234073 . _:b531234107 "2"^^ . _:b531234071 . _:b24815025 . _:b531234106 "2"^^ . _:b531234070 . _:b24815016 "Importantly, SLUG expression in clinical samples was significantly higher after the development of acquired resistance to EGFR TKIs than in treatment-na\u00EFve samples>>42<<." . _:b531234065 . . _:b24815023 . _:b531233988 . _:b531234064 . . . _:b531234067 . _:b531234005 . _:b531234066 . _:b531234112 . _:b531234077 . . _:b24815026 . _:b531234112 "2"^^ . "10.1038%2Fsrep02560" . _:b531234076 . . . _:b531234079 . _:b24815006 . _:b531234078 . _:b531234073 . _:b24815027 . _:b531233972 . . _:b531234072 . . . _:b531234075 . _:b531234084 . _:b531234080 . _:b531234085 . _:b531234074 . _:b531234086 . _:b531234087 . _:b531234080 . _:b531234081 . _:b531234108 . _:b531234085 . _:b531234082 . . _:b531234083 . _:b531234092 . _:b531234093 . _:b531234084 . _:b531234094 . _:b531234095 . _:b531234088 . _:b531234089 . _:b531234087 . _:b531234090 . _:b531234091 . _:b531234100 . _:b531233998 . _:b531234096 . _:b531234086 . _:b531234101 . _:b531234102 . _:b531234103 . _:b531234096 . _:b531234097 . _:b531234081 . _:b531234098 . _:b531234099 . _:b531234108 . . _:b531234109 . _:b531234080 . _:b531234110 . _:b531234111 . _:b531234104 . _:b531234105 . _:b531234083 . _:b531234106 . _:b531234107 . _:b531234052 . _:b24815020 "Earlier studies have suggested an active involvement of EMT in resistance to EGFR TKIs>>25274344<<, and accordingly, E-cadherin expression has been reported to operate as a biomarker capable of predicting the clinical efficacy of gefitinib27." . . _:b531234053 . _:b531234082 . . _:b531234054 . . _:b531234055 . . _:b531234048 . _:b531233994 . _:b531234026 . _:b531234049 . _:b531234093 . _:b531234082 . _:b531234050 . _:b531234051 . _:b531234060 . . _:b531234061 . _:b531234092 . _:b531234062 . _:b531234063 . _:b531234056 . . _:b531234057 . _:b531234095 . . _:b531234058 . _:b531234078 . _:b531234059 . . _:b531234068 . . _:b531234069 . _:b531234094 . . _:b531234070 . _:b531234071 . _:b531234064 . _:b531234065 . _:b531234089 . _:b531234066 . _:b531234067 . . _:b531234076 . _:b531234077 . _:b531234088 . . _:b531234078 . _:b531234079 . _:b531234072 . _:b531234073 . _:b531234091 . _:b531234074 . _:b24815035 "Through using a milk thistle extract rich in silybin meglumine, a commercially used water-soluble form of silibinin>>57<<, we are currently testing whether the anti-IGF-1R/EMT activity of silibinin can translate into the reversal of acquired resistance to EGFR TKIs in animal models." . _:b531234075 . _:b531234048 . . _:b531234090 . _:b531233963 . _:b531234101 . _:b531233973 . . _:b531234100 . . . _:b531234103 . . _:b24815007 "kinase activity levels, IGF-1R is among a small group of oncogenes that can confer in vivo tumorigenicity when overexpressed alone via IGFR-1R-mediated induction of the transcriptional repressor SNAIL and downregulation of E-cadherin>>35<<. Indeed, recent results from our laboratory have confirmed that regardless of erlotinib treatment, EMT-enriched erlotinib-resistant PC-9 tumor xenografts exhibited a significantly enhanced tumor engraftment and faster growth compared with" . . _:b531233999 . _:b531234102 . . _:b531233992 . _:b24815002 "that clinical trials of IGF-1R inhibitors with demonstrated activity in unselected NSCLC patients might play a role in association with EGFR inhibitors in the management of NSCLCs with acquired resistance to gefitinib/erlotinib>>32<<33. It should be noted that increased IGF-1R activation in erlotinib-refractory delE746-A750-mutated PC-9 cells occurred in our lab models independently of changes in IGF-binding proteins (IGFBPs) (data not shown)." . _:b531234106 . _:b531234097 . . _:b531234096 . . _:b531234099 . . _:b531234098 . _:b531234019 . _:b531234109 . _:b531233980 . _:b24815014 . _:b531234108 . . . _:b531234009 . _:b531234111 . _:b531234110 . _:b24815033 "Silibinin has been shown to reduce IGF-1R phosphorylation, indicating an inhibitory effect on the IGF-1R-mediated signaling pathway in cancer cells>>55<<56. Through using a milk thistle extract rich in silybin meglumine, a commercially used water-soluble form of silibinin57, we are currently testing whether the anti-IGF-1R/EMT activity of silibinin can translate into the reversal of" . _:b24815005 "Whereas earlier studies have demonstrated that a loss of IGFBP (IGFBP-3 and IGFBP-4) expression levels in tumor cells treated with EGFR TKIs activated IGF-1R signaling, which in turn mediated resistance to an EGFR antagonist>>2031<<, our analyses failed to detect significant changes in the secretion levels of IGFBPs in delE746-A750-mutated PC-9 cells with acquired resistance to erlotinib." . _:b531234105 . _:b531234085 . _:b531234012 . _:b531234104 . _:b24815026 "In this regard, it is worth noting that a landmark study showing that the addition of silibinin, which is the active constituent of silymarin isolated from the dried fruits of milk thistle (Silybum marianum) plant>>4748<<4950, to EGFR TKIs drastically suppresses tumor growth in primary and acquired-resistance cells with the EGFR T790M mutation51 may open a new therapeutic avenue to clinically manage EMT-driven acquired resistance to erlotinib." . _:b531234107 . . _:b531234106 . _:b24815006 "NSCLC responses to IGF-1R inhibition revealed that intrinsic sensitivity to figitumumab, a monoclonal antibody against IGF-1R, was significantly related to the simultaneous occurrence of markers of the IGF-1R pathway in the EMT pathway>>34<<. Although it remains unclear whether high-levels of IGF-1R expression are directly associated with high IGF-1R kinase activity levels, IGF-1R is among a small group of oncogenes that can confer in vivo tumorigenicity when overexpressed" . . _:b531234047 . _:b531233962 . _:b531234072 . _:b531233970 . . _:b531234075 . _:b24815014 "of NSCLC cells intrinsically resistant to erlotinib that display features suggestive of EMT. Using the erlotinib-sensitive EGFR mutant NSCLC cell line HCC4006 harboring the delL747-E749, A750P mutation in EGFR exon 19, Suda et al.>>29<< established that mesenchymal status, not a specific oncogenic-activated protein, could sufficiently promote loss of EGFR dependence to confer resistance to erlotinib." . . _:b531233965 . _:b531234112 . _:b24815022 . . . . . . _:b24815011 "implication in the EMT phenomenon, EMT transcriptional drivers (e.g., SNAIL factors) can also regulate other cellular processes related to cell proliferation and survival, thus contributing to resistance to pro-apoptotic stresses>>36373839<<. Accordingly, we recently revealed that a significant reduction in tumor growth and dramatic gain in sensitivity to the growth-inhibitory effects of the anti-HER2 monoclonal antibody trastuzumab in vivo can be observed upon injection of" . _:b24815020 . _:b24815003 . . _:b24815034 "Silibinin has been shown to reduce IGF-1R phosphorylation, indicating an inhibitory effect on the IGF-1R-mediated signaling pathway in cancer cells>>5556<<. Through using a milk thistle extract rich in silybin meglumine, a commercially used water-soluble form of silibinin57, we are currently testing whether the anti-IGF-1R/EMT activity of silibinin can translate into the reversal of acquired" . . . _:b531234040 . . _:b531234038 . _:b531234069 . _:b531234100 . _:b531234024 . _:b531233995 . . _:b24815005 . . _:b531234065 . _:b531234064 . . _:b24815001 . . _:b531233990 . _:b531234027 . _:b531234068 . . . . _:b24815017 . _:b531233975 . _:b531234025 . _:b531234097 . _:b24815016 . _:b24815011 . _:b24815015 . . _:b531234110 . _:b531234052 . . _:b531234034 . _:b531234016 . . . _:b24815017 "Earlier studies have suggested an active involvement of EMT in resistance to EGFR TKIs>>25<<274344, and accordingly, E-cadherin expression has been reported to operate as a biomarker capable of predicting the clinical efficacy of gefitinib27." . _:b531233984 . _:b24815019 "Earlier studies have suggested an active involvement of EMT in resistance to EGFR TKIs>>252743<<44, and accordingly, E-cadherin expression has been reported to operate as a biomarker capable of predicting the clinical efficacy of gefitinib27." . _:b531233996 . . _:b24815028 . _:b531234014 . . _:b24815012 "a significant reduction in tumor growth and dramatic gain in sensitivity to the growth-inhibitory effects of the anti-HER2 monoclonal antibody trastuzumab in vivo can be observed upon injection of SLUG knocked-down cells into nude mice>>40<<. The promotion of cell survival as a primary function of EMT factors such as SLUG, which can rescue cells from apoptosis by repressing pro-apoptotic factors that otherwise would promote cell death during a partial EMT, is strongly" . . _:b24815001 "While preparing this manuscript, Cortot et al.>>31<< reported that PC-9-derived clones with acquired resistance to mutant-selective EGFR inhibitors and irreversible quinazoline EGFR inhibitors in the absence of EGFR T790M demonstrate a significantly activated IGF-1R signaling, and" . . . _:b531234030 . _:b531233976 . _:b24815002 . _:b531234000 . . _:b24815030 . . . _:b531234079 . . _:b531233965 . . _:b531233964 . . _:b531233968 . _:b531233967 . . . _:b531234006 . _:b531233966 . . . . . . _:b531234017 . _:b24815000 _:b24815004 . . _:b24815000 _:b24815005 . _:b531234066 . _:b24815000 _:b24815006 . _:b24815000 _:b24815007 . _:b531233963 . _:b531234008 . _:b24815000 _:b24815001 . _:b24815000 _:b24815002 . _:b531234061 . _:b24815000 _:b24815003 . _:b24815030 "Silibinin appears to operate as a potent natural agent leading to the reversal of EMT by decreasing the levels of key EMT TFs (e.g., SLUG) and increasing the expression levels of E-cadherin>>52<<5354. Silibinin has been shown to reduce IGF-1R phosphorylation, indicating an inhibitory effect on the IGF-1R-mediated signaling pathway in cancer cells5556. Through using a milk thistle extract rich in silybin meglumine, a commercially" . _:b531233962 . . _:b24815000 _:b24815012 . _:b24815000 _:b24815013 . _:b531234077 . . _:b24815000 _:b24815014 . _:b531233973 . _:b24815000 _:b24815015 . . _:b24815000 _:b24815008 . _:b24815000 _:b24815009 . _:b531234011 . _:b24815000 _:b24815010 . _:b531233972 . _:b24815000 _:b24815011 . _:b24815000 _:b24815020 . _:b531234062 . _:b24815000 _:b24815021 . _:b24815000 _:b24815022 . _:b531233975 . _:b24815000 _:b24815023 . _:b24815000 _:b24815016 . _:b24815000 _:b24815017 . _:b24815000 _:b24815018 . _:b24815019 . _:b531233974 . _:b24815000 _:b24815019 . _:b24815000 _:b24815028 . _:b24815000 _:b24815029 . _:b24815000 _:b24815030 . _:b531233969 . . _:b24815000 _:b24815031 . _:b531234031 . _:b24815000 _:b24815024 . _:b24815000 _:b24815025 . . _:b24815000 _:b24815026 . _:b531233968 . _:b24815000 _:b24815027 . _:b24815000 _:b24815036 . _:b24815036 . _:b24815000 _:b24815037 . . _:b24815000 _:b24815038 . _:b531233971 . _:b24815000 _:b24815032 . _:b24815034 . . _:b24815000 _:b24815033 . _:b24815000 _:b24815034 . _:b531233970 . _:b24815000 _:b24815035 . _:b531233964 . _:b531233981 . _:b531234111 . _:b531234099 . _:b531234002 . . _:b531233980 . _:b531234107 . . _:b531233983 . _:b24815009 . . _:b531233981 . _:b531233982 . _:b24815008 "direct implication in the EMT phenomenon, EMT transcriptional drivers (e.g., SNAIL factors) can also regulate other cellular processes related to cell proliferation and survival, thus contributing to resistance to pro-apoptotic stresses>>36<<373839. Accordingly, we recently revealed that a significant reduction in tumor growth and dramatic gain in sensitivity to the growth-inhibitory effects of the anti-HER2 monoclonal antibody trastuzumab in vivo can be observed upon" . _:b531234089 . _:b531233977 . . _:b531233976 . . _:b531233979 . _:b531233978 . _:b531234056 . _:b531234023 . _:b531233989 . _:b24815022 "A microRNA gene expression signature targeting EMT has been recently shown to predict response to erlotinib>>45<<. Byers et al.46 recently developed a robust EMT signature that highlights different drug responsiveness patterns for epithelial and mesenchymal NSCLC cells and can predict resistance to EGFR TKIs regardless of EGFR mutation status. It" . _:b531233988 . _:b531233991 . . _:b24815025 "In this regard, it is worth noting that a landmark study showing that the addition of silibinin, which is the active constituent of silymarin isolated from the dried fruits of milk thistle (Silybum marianum) plant>>47<<484950, to EGFR TKIs drastically suppresses tumor growth in primary and acquired-resistance cells with the EGFR T790M mutation51 may open a new therapeutic avenue to clinically manage EMT-driven acquired resistance to erlotinib." . _:b531233990 . . . _:b531233985 . . _:b531233984 . _:b531234049 . _:b24815036 "A dual targeting of IGF-1R and EMT might be crucial to prevent and/or circumvent acquired resistance to erlotinib in EGFR-mutated cells because, although early studies by Morgillo et al.>>58<< provided evidence that erlotinib induces heterodimerization of EGFR/IGF-1R, we failed to observe either co-localization of the phospho-active forms of EGFR and IGF-1R or changes in the phosphorylation status of EGFR upon pharmacological" . . _:b531233987 . _:b531233986 . _:b531234033 . . _:b531233997 . . _:b531233996 . . . _:b531233999 . _:b531233966 "6"^^ . . _:b531234101 . _:b531233998 . _:b531233982 . _:b531233993 . _:b531233964 "6"^^ . . _:b531233967 "5"^^ . . _:b531233992 . _:b531233965 "6"^^ . _:b531233995 . _:b24815013 . _:b531233962 "8"^^ . _:b531233994 . _:b531233963 "7"^^ . . _:b531234005 . _:b531233978 . _:b531234004 . . _:b531234007 . _:b531233989 . _:b531234010 . _:b531233973 "4"^^ . . _:b531234006 .