Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling
EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR-activating mutations. However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistanc...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2013-10, Vol.73 (20), p.6243-6253 |
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| creator | KANDA, Rina KAWAHARA, Akihiko KUWANO, Michihiko ONO, Mayumi WATARI, Kosuke MURAKAMI, Yuichi SONODA, Kahori MAEDA, Masashi FUJITA, Hideaki KAGE, Masayoshi URAMOTO, Hidetaka COSTA, Carlota |
| description | EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR-activating mutations. However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrin β1, α2, and α5 along with enhanced cell adhesion activity. Interestingly, RNAi-mediated silencing of integrin β1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Furthermore, Src silencing inhibited Akt phosphorylation and cell growth, with this inhibitory effect further augmented by erlotinib treatment. Increased expression of integrin β1, α5, and/or α2 was also observed in refractory tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, our findings identify the integrin β1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs. |
| doi_str_mv | 10.1158/0008-5472.can-12-4502 |
| format | Article |
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However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrin β1, α2, and α5 along with enhanced cell adhesion activity. Interestingly, RNAi-mediated silencing of integrin β1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Furthermore, Src silencing inhibited Akt phosphorylation and cell growth, with this inhibitory effect further augmented by erlotinib treatment. Increased expression of integrin β1, α5, and/or α2 was also observed in refractory tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, our findings identify the integrin β1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-12-4502</identifier><identifier>PMID: 23872583</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Antineoplastic agents ; Biological and medical sciences ; Cell Adhesion - drug effects ; Cell Adhesion - physiology ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; Erlotinib Hydrochloride ; Gene Knockdown Techniques ; Humans ; Integrin beta1 - genetics ; Integrin beta1 - metabolism ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Medical sciences ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Oncogene Protein v-akt - metabolism ; Pharmacology. Drug treatments ; Pneumology ; Protein Kinase Inhibitors - pharmacology ; Quinazolines - pharmacology ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Receptor, Epidermal Growth Factor - genetics ; Receptor, Epidermal Growth Factor - metabolism ; Signal Transduction ; src-Family Kinases - metabolism ; Tumors ; Tumors of the respiratory system and mediastinum</subject><ispartof>Cancer research (Chicago, Ill.), 2013-10, Vol.73 (20), p.6243-6253</ispartof><rights>2014 INIST-CNRS</rights><rights>2013 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c452t-4fc7932b4d537419bd8ff5d014814b917779d062944f2d03cd69f2ab98a446593</citedby><cites>FETCH-LOGICAL-c452t-4fc7932b4d537419bd8ff5d014814b917779d062944f2d03cd69f2ab98a446593</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27834233$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23872583$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KANDA, Rina</creatorcontrib><creatorcontrib>KAWAHARA, Akihiko</creatorcontrib><creatorcontrib>KUWANO, Michihiko</creatorcontrib><creatorcontrib>ONO, Mayumi</creatorcontrib><creatorcontrib>WATARI, Kosuke</creatorcontrib><creatorcontrib>MURAKAMI, Yuichi</creatorcontrib><creatorcontrib>SONODA, Kahori</creatorcontrib><creatorcontrib>MAEDA, Masashi</creatorcontrib><creatorcontrib>FUJITA, Hideaki</creatorcontrib><creatorcontrib>KAGE, Masayoshi</creatorcontrib><creatorcontrib>URAMOTO, Hidetaka</creatorcontrib><creatorcontrib>COSTA, Carlota</creatorcontrib><title>Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR-activating mutations. 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Together, our findings identify the integrin β1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs.</description><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Adhesion - drug effects</subject><subject>Cell Adhesion - physiology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Drug Resistance, Neoplasm</subject><subject>Erlotinib Hydrochloride</subject><subject>Gene Knockdown Techniques</subject><subject>Humans</subject><subject>Integrin beta1 - genetics</subject><subject>Integrin beta1 - metabolism</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Medical sciences</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Oncogene Protein v-akt - metabolism</subject><subject>Pharmacology. Drug treatments</subject><subject>Pneumology</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Quinazolines - pharmacology</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Receptor, Epidermal Growth Factor - genetics</subject><subject>Receptor, Epidermal Growth Factor - metabolism</subject><subject>Signal Transduction</subject><subject>src-Family Kinases - metabolism</subject><subject>Tumors</subject><subject>Tumors of the respiratory system and mediastinum</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkMtu2zAQRYmiQeO4_YQW3BToRjYfQ5NaOorzAJwEaNo1QZGUwVamHVIq4N_Kh-SbKiFOshpc4NyZwUHoKyUzSoWaE0JUIUCymTWxoKwAQdgHNKGCq0ICiI9o8sacorOc_wxRUCI-oVPGlWRC8QmqV6nddSGGGv_0OeTOROtxiHjdxw2uxpRw5ds241vvgum8w_UB38TOb9KAPT_R-UOy8-XfrrhI4Z-P-PywNznjh7CJpg1x8xmdNKbN_stxTtHvy9Wv6rpY31_dVMt1YUGwroDGypKzGpzgEmhZO9U0whEKikJdUill6ciClQANc4RbtygbZupSGYCFKPkU_XjZu0-7x97nTm9DtsPrJvpdnzUF4MAE42xAxQtq0y7n5Bu9T2Fr0kFToke9elSnR3W6Wt5pyvSod-h9O57o6613b61XnwPw_QiYbE3bpEFgyO-cVMMLnPP_SVGCMQ</recordid><startdate>20131015</startdate><enddate>20131015</enddate><creator>KANDA, Rina</creator><creator>KAWAHARA, Akihiko</creator><creator>KUWANO, Michihiko</creator><creator>ONO, Mayumi</creator><creator>WATARI, Kosuke</creator><creator>MURAKAMI, Yuichi</creator><creator>SONODA, Kahori</creator><creator>MAEDA, Masashi</creator><creator>FUJITA, Hideaki</creator><creator>KAGE, Masayoshi</creator><creator>URAMOTO, Hidetaka</creator><creator>COSTA, Carlota</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20131015</creationdate><title>Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling</title><author>KANDA, Rina ; KAWAHARA, Akihiko ; KUWANO, Michihiko ; ONO, Mayumi ; WATARI, Kosuke ; MURAKAMI, Yuichi ; SONODA, Kahori ; MAEDA, Masashi ; FUJITA, Hideaki ; KAGE, Masayoshi ; URAMOTO, Hidetaka ; COSTA, Carlota</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c452t-4fc7932b4d537419bd8ff5d014814b917779d062944f2d03cd69f2ab98a446593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cell Adhesion - drug effects</topic><topic>Cell Adhesion - physiology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Drug Resistance, Neoplasm</topic><topic>Erlotinib Hydrochloride</topic><topic>Gene Knockdown Techniques</topic><topic>Humans</topic><topic>Integrin beta1 - genetics</topic><topic>Integrin beta1 - metabolism</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Medical sciences</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Oncogene Protein v-akt - metabolism</topic><topic>Pharmacology. 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However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes. In erlotinib-resistant lung cancer cells harboring activating EGFR mutations that we established, there was increased expression of Src, integrin β1, α2, and α5 along with enhanced cell adhesion activity. Interestingly, RNAi-mediated silencing of integrin β1 restored erlotinib sensitivity and reduced activation of Src and Akt after erlotinib treatment. Furthermore, Src silencing inhibited Akt phosphorylation and cell growth, with this inhibitory effect further augmented by erlotinib treatment. Increased expression of integrin β1, α5, and/or α2 was also observed in refractory tumor samples from patients with lung cancer treated with erlotinib and/or gefitinib. Together, our findings identify the integrin β1/Src/Akt signaling pathway as a key mediator of acquired resistance to EGFR-targeted anticancer drugs.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>23872583</pmid><doi>10.1158/0008-5472.can-12-4502</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2013-10, Vol.73 (20), p.6243-6253 |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals |
| subjects | Antineoplastic agents Biological and medical sciences Cell Adhesion - drug effects Cell Adhesion - physiology Cell Line, Tumor Cell Proliferation Drug Resistance, Neoplasm Erlotinib Hydrochloride Gene Knockdown Techniques Humans Integrin beta1 - genetics Integrin beta1 - metabolism Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Medical sciences Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Oncogene Protein v-akt - metabolism Pharmacology. Drug treatments Pneumology Protein Kinase Inhibitors - pharmacology Quinazolines - pharmacology Receptor, Epidermal Growth Factor - antagonists & inhibitors Receptor, Epidermal Growth Factor - genetics Receptor, Epidermal Growth Factor - metabolism Signal Transduction src-Family Kinases - metabolism Tumors Tumors of the respiratory system and mediastinum |
| title | Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling |
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