Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines
Colorectal cancer; Epidermal growth factor receptor (EGFR); MAPK pathway Càncer colorectal; Receptor epidèrmic de factor del creixement (EGFR); Via MAPK Cáncer colorrectal; Receptor epidérmico de factor del crecimiento (EGFR); Vía MAPK BACKGROUND: Previous studies showed that the combination of an a...
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| creator | Vitiello, Pietro Paolo Cardone, Claudia Martini, Giulia Ciardiello, Davide Belli, Valentina Matrone, Nunzia |
| description | Colorectal cancer; Epidermal growth factor receptor (EGFR); MAPK pathway
Càncer colorectal; Receptor epidèrmic de factor del creixement (EGFR); Via MAPK
Cáncer colorrectal; Receptor epidérmico de factor del crecimiento (EGFR); Vía MAPK
BACKGROUND:
Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC.
METHODS:
We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones.
RESULTS:
We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors.
CONCLUSIONS:
PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R. |
| format | Article |
| fullrecord | <record><control><sourceid>csuc_XX2</sourceid><recordid>TN_cdi_csuc_recercat_oai_recercat_cat_11351_3831</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>oai_recercat_cat_11351_3831</sourcerecordid><originalsourceid>FETCH-csuc_recercat_oai_recercat_cat_11351_38313</originalsourceid><addsrcrecordid>eNqdTkFKxEAQzMWDqH-oD4Q1DILXRXZVgrBE76Hp9JLBycww3VnZZ_lDZ0Hw7qEoqqgq6rr5HoQlWyqwc0nqo-DTR1JpJ8kSJ4mGw6vrQWz-ROZThFdQhChTFizCM0WvCyzhJMU8U4CuORdRvcTTETYLds_7YTNs3zdv20OPTDZ_0Rk-oq9mu6xGJhPmdanbnEIqwlaXmCJLAUsICPWe3jZXRwoqd79809zvdx9PLy3rymNtSWGyMZH_Exd0nXvoRvfoOvePyg-OVmag</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines</title><source>Recercat</source><creator>Vitiello, Pietro Paolo ; Cardone, Claudia ; Martini, Giulia ; Ciardiello, Davide ; Belli, Valentina ; Matrone, Nunzia</creator><creatorcontrib>Vitiello, Pietro Paolo ; Cardone, Claudia ; Martini, Giulia ; Ciardiello, Davide ; Belli, Valentina ; Matrone, Nunzia</creatorcontrib><description>Colorectal cancer; Epidermal growth factor receptor (EGFR); MAPK pathway
Càncer colorectal; Receptor epidèrmic de factor del creixement (EGFR); Via MAPK
Cáncer colorrectal; Receptor epidérmico de factor del crecimiento (EGFR); Vía MAPK
BACKGROUND:
Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC.
METHODS:
We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones.
RESULTS:
We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors.
CONCLUSIONS:
PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R.</description><language>eng</language><publisher>BMC</publisher><subject>antagonistas & inhibidores ; antagonists & inhibitors ; CHEMICALS AND DRUGS ; Colorectal Neoplasms ; COMPUESTOS QUÍMICOS Y DROGAS ; Còlon - Càncer ; Digestive System Diseases ; Digestive System Neoplasms ; DISEASES ; ENFERMEDADES ; Enfermedades del Sistema Digestivo ; Enzimas ; Enzimas y Coenzimas ; Enzymes ; Enzymes and Coenzymes ; Epidermal Growth Factor ; Factor de creixement epidèrmic - Inhibidors ; factor de crecimiento epidérmico ; Fosfotransferasas ; Fosfotransferasas (Aceptor de Grupo Alcohol) ; Gastrointestinal Hormones ; Gastrointestinal Neoplasms ; hormonas ; hormonas, sustitutos de hormonas y antagonistas de hormonas ; hormonas gastrointestinales ; Hormones ; Hormones, Hormone Substitutes, and Hormone Antagonists ; Intestinal Neoplasms ; MAP Kinase Kinase Kinases ; microbiology ; microbiología ; Neoplasias Colorrectales ; Neoplasias del Sistema Digestivo ; Neoplasias Gastrointestinales ; Neoplasias Intestinales ; Other subheadings ; Otros calificadores ; Phosphotransferases ; Phosphotransferases (Alcohol Group Acceptor) ; Protein-Serine-Threonine Kinases ; Protein Kinases ; Proteínas Quinasas ; Proteínas Serina-Treonina Quinasas ; Proteïnes quinases activades per mitògens - Inhibidors ; Quinasas Quinasa Quinasa PAM ; Transferasas ; Transferases</subject><creationdate>2019-01</creationdate><rights>Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,776,881,26951</link.rule.ids><linktorsrc>$$Uhttps://recercat.cat/handle/11351/3831$$EView_record_in_Consorci_de_Serveis_Universitaris_de_Catalunya_(CSUC)$$FView_record_in_$$GConsorci_de_Serveis_Universitaris_de_Catalunya_(CSUC)$$Hfree_for_read</linktorsrc></links><search><creatorcontrib>Vitiello, Pietro Paolo</creatorcontrib><creatorcontrib>Cardone, Claudia</creatorcontrib><creatorcontrib>Martini, Giulia</creatorcontrib><creatorcontrib>Ciardiello, Davide</creatorcontrib><creatorcontrib>Belli, Valentina</creatorcontrib><creatorcontrib>Matrone, Nunzia</creatorcontrib><title>Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines</title><description>Colorectal cancer; Epidermal growth factor receptor (EGFR); MAPK pathway
Càncer colorectal; Receptor epidèrmic de factor del creixement (EGFR); Via MAPK
Cáncer colorrectal; Receptor epidérmico de factor del crecimiento (EGFR); Vía MAPK
BACKGROUND:
Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC.
METHODS:
We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones.
RESULTS:
We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors.
CONCLUSIONS:
PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R.</description><subject>antagonistas & inhibidores</subject><subject>antagonists & inhibitors</subject><subject>CHEMICALS AND DRUGS</subject><subject>Colorectal Neoplasms</subject><subject>COMPUESTOS QUÍMICOS Y DROGAS</subject><subject>Còlon - Càncer</subject><subject>Digestive System Diseases</subject><subject>Digestive System Neoplasms</subject><subject>DISEASES</subject><subject>ENFERMEDADES</subject><subject>Enfermedades del Sistema Digestivo</subject><subject>Enzimas</subject><subject>Enzimas y Coenzimas</subject><subject>Enzymes</subject><subject>Enzymes and Coenzymes</subject><subject>Epidermal Growth Factor</subject><subject>Factor de creixement epidèrmic - Inhibidors</subject><subject>factor de crecimiento epidérmico</subject><subject>Fosfotransferasas</subject><subject>Fosfotransferasas (Aceptor de Grupo Alcohol)</subject><subject>Gastrointestinal Hormones</subject><subject>Gastrointestinal Neoplasms</subject><subject>hormonas</subject><subject>hormonas, sustitutos de hormonas y antagonistas de hormonas</subject><subject>hormonas gastrointestinales</subject><subject>Hormones</subject><subject>Hormones, Hormone Substitutes, and Hormone Antagonists</subject><subject>Intestinal Neoplasms</subject><subject>MAP Kinase Kinase Kinases</subject><subject>microbiology</subject><subject>microbiología</subject><subject>Neoplasias Colorrectales</subject><subject>Neoplasias del Sistema Digestivo</subject><subject>Neoplasias Gastrointestinales</subject><subject>Neoplasias Intestinales</subject><subject>Other subheadings</subject><subject>Otros calificadores</subject><subject>Phosphotransferases</subject><subject>Phosphotransferases (Alcohol Group Acceptor)</subject><subject>Protein-Serine-Threonine Kinases</subject><subject>Protein Kinases</subject><subject>Proteínas Quinasas</subject><subject>Proteínas Serina-Treonina Quinasas</subject><subject>Proteïnes quinases activades per mitògens - Inhibidors</subject><subject>Quinasas Quinasa Quinasa PAM</subject><subject>Transferasas</subject><subject>Transferases</subject><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>XX2</sourceid><recordid>eNqdTkFKxEAQzMWDqH-oD4Q1DILXRXZVgrBE76Hp9JLBycww3VnZZ_lDZ0Hw7qEoqqgq6rr5HoQlWyqwc0nqo-DTR1JpJ8kSJ4mGw6vrQWz-ROZThFdQhChTFizCM0WvCyzhJMU8U4CuORdRvcTTETYLds_7YTNs3zdv20OPTDZ_0Rk-oq9mu6xGJhPmdanbnEIqwlaXmCJLAUsICPWe3jZXRwoqd79809zvdx9PLy3rymNtSWGyMZH_Exd0nXvoRvfoOvePyg-OVmag</recordid><startdate>20190128</startdate><enddate>20190128</enddate><creator>Vitiello, Pietro Paolo</creator><creator>Cardone, Claudia</creator><creator>Martini, Giulia</creator><creator>Ciardiello, Davide</creator><creator>Belli, Valentina</creator><creator>Matrone, Nunzia</creator><general>BMC</general><scope>XX2</scope></search><sort><creationdate>20190128</creationdate><title>Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines</title><author>Vitiello, Pietro Paolo ; Cardone, Claudia ; Martini, Giulia ; Ciardiello, Davide ; Belli, Valentina ; Matrone, Nunzia</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-csuc_recercat_oai_recercat_cat_11351_38313</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>antagonistas & inhibidores</topic><topic>antagonists & inhibitors</topic><topic>CHEMICALS AND DRUGS</topic><topic>Colorectal Neoplasms</topic><topic>COMPUESTOS QUÍMICOS Y DROGAS</topic><topic>Còlon - Càncer</topic><topic>Digestive System Diseases</topic><topic>Digestive System Neoplasms</topic><topic>DISEASES</topic><topic>ENFERMEDADES</topic><topic>Enfermedades del Sistema Digestivo</topic><topic>Enzimas</topic><topic>Enzimas y Coenzimas</topic><topic>Enzymes</topic><topic>Enzymes and Coenzymes</topic><topic>Epidermal Growth Factor</topic><topic>Factor de creixement epidèrmic - Inhibidors</topic><topic>factor de crecimiento epidérmico</topic><topic>Fosfotransferasas</topic><topic>Fosfotransferasas (Aceptor de Grupo Alcohol)</topic><topic>Gastrointestinal Hormones</topic><topic>Gastrointestinal Neoplasms</topic><topic>hormonas</topic><topic>hormonas, sustitutos de hormonas y antagonistas de hormonas</topic><topic>hormonas gastrointestinales</topic><topic>Hormones</topic><topic>Hormones, Hormone Substitutes, and Hormone Antagonists</topic><topic>Intestinal Neoplasms</topic><topic>MAP Kinase Kinase Kinases</topic><topic>microbiology</topic><topic>microbiología</topic><topic>Neoplasias Colorrectales</topic><topic>Neoplasias del Sistema Digestivo</topic><topic>Neoplasias Gastrointestinales</topic><topic>Neoplasias Intestinales</topic><topic>Other subheadings</topic><topic>Otros calificadores</topic><topic>Phosphotransferases</topic><topic>Phosphotransferases (Alcohol Group Acceptor)</topic><topic>Protein-Serine-Threonine Kinases</topic><topic>Protein Kinases</topic><topic>Proteínas Quinasas</topic><topic>Proteínas Serina-Treonina Quinasas</topic><topic>Proteïnes quinases activades per mitògens - Inhibidors</topic><topic>Quinasas Quinasa Quinasa PAM</topic><topic>Transferasas</topic><topic>Transferases</topic><toplevel>online_resources</toplevel><creatorcontrib>Vitiello, Pietro Paolo</creatorcontrib><creatorcontrib>Cardone, Claudia</creatorcontrib><creatorcontrib>Martini, Giulia</creatorcontrib><creatorcontrib>Ciardiello, Davide</creatorcontrib><creatorcontrib>Belli, Valentina</creatorcontrib><creatorcontrib>Matrone, Nunzia</creatorcontrib><collection>Recercat</collection></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext_linktorsrc</fulltext></delivery><addata><au>Vitiello, Pietro Paolo</au><au>Cardone, Claudia</au><au>Martini, Giulia</au><au>Ciardiello, Davide</au><au>Belli, Valentina</au><au>Matrone, Nunzia</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines</atitle><date>2019-01-28</date><risdate>2019</risdate><abstract>Colorectal cancer; Epidermal growth factor receptor (EGFR); MAPK pathway
Càncer colorectal; Receptor epidèrmic de factor del creixement (EGFR); Via MAPK
Cáncer colorrectal; Receptor epidérmico de factor del crecimiento (EGFR); Vía MAPK
BACKGROUND:
Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC.
METHODS:
We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones.
RESULTS:
We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors.
CONCLUSIONS:
PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R.</abstract><pub>BMC</pub><oa>free_for_read</oa></addata></record> |
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| subjects | antagonistas & inhibidores antagonists & inhibitors CHEMICALS AND DRUGS Colorectal Neoplasms COMPUESTOS QUÍMICOS Y DROGAS Còlon - Càncer Digestive System Diseases Digestive System Neoplasms DISEASES ENFERMEDADES Enfermedades del Sistema Digestivo Enzimas Enzimas y Coenzimas Enzymes Enzymes and Coenzymes Epidermal Growth Factor Factor de creixement epidèrmic - Inhibidors factor de crecimiento epidérmico Fosfotransferasas Fosfotransferasas (Aceptor de Grupo Alcohol) Gastrointestinal Hormones Gastrointestinal Neoplasms hormonas hormonas, sustitutos de hormonas y antagonistas de hormonas hormonas gastrointestinales Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Intestinal Neoplasms MAP Kinase Kinase Kinases microbiology microbiología Neoplasias Colorrectales Neoplasias del Sistema Digestivo Neoplasias Gastrointestinales Neoplasias Intestinales Other subheadings Otros calificadores Phosphotransferases Phosphotransferases (Alcohol Group Acceptor) Protein-Serine-Threonine Kinases Protein Kinases Proteínas Quinasas Proteínas Serina-Treonina Quinasas Proteïnes quinases activades per mitògens - Inhibidors Quinasas Quinasa Quinasa PAM Transferasas Transferases |
| title | Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines |
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