Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab
In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resis...
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| Veröffentlicht in: | Clinical cancer research 2015-07, Vol.21 (13), p.2975-2983 |
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| creator | Napolitano, Stefania Martini, Giulia Rinaldi, Barbara Martinelli, Erika Donniacuo, Maria Berrino, Liberato Vitagliano, Donata Morgillo, Floriana Barra, Giusy De Palma, Raffaele Merolla, Francesco Ciardiello, Fortunato Troiani, Teresa |
| description | In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance.
We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).
Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.
The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients. |
| doi_str_mv | 10.1158/1078-0432.CCR-15-0020 |
| format | Article |
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We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).
Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.
The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-15-0020</identifier><identifier>PMID: 25838391</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Apoptosis - drug effects ; Cetuximab - administration & dosage ; Colorectal Neoplasms - drug therapy ; Drug Resistance, Neoplasm - drug effects ; Drug Synergism ; Female ; HCT116 Cells ; Humans ; Mice, Inbred BALB C ; Mice, Nude ; Phenylurea Compounds - administration & dosage ; Pyridines - administration & dosage ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; Xenograft Model Antitumor Assays</subject><ispartof>Clinical cancer research, 2015-07, Vol.21 (13), p.2975-2983</ispartof><rights>2015 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-27296865f76202c9484beb86b3bd5efedc42f2d70caaa32f9a21908332658e573</citedby><cites>FETCH-LOGICAL-c356t-27296865f76202c9484beb86b3bd5efedc42f2d70caaa32f9a21908332658e573</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3354,27922,27923</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25838391$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Napolitano, Stefania</creatorcontrib><creatorcontrib>Martini, Giulia</creatorcontrib><creatorcontrib>Rinaldi, Barbara</creatorcontrib><creatorcontrib>Martinelli, Erika</creatorcontrib><creatorcontrib>Donniacuo, Maria</creatorcontrib><creatorcontrib>Berrino, Liberato</creatorcontrib><creatorcontrib>Vitagliano, Donata</creatorcontrib><creatorcontrib>Morgillo, Floriana</creatorcontrib><creatorcontrib>Barra, Giusy</creatorcontrib><creatorcontrib>De Palma, Raffaele</creatorcontrib><creatorcontrib>Merolla, Francesco</creatorcontrib><creatorcontrib>Ciardiello, Fortunato</creatorcontrib><creatorcontrib>Troiani, Teresa</creatorcontrib><title>Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>In colorectal cancer, the activation of the intracellular RAS-RAF and PIK3CA-AKT pathways has been implicated in the resistance to anti-EGFR mAbs. We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance.
We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).
Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.
The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Apoptosis - drug effects</subject><subject>Cetuximab - administration & dosage</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Synergism</subject><subject>Female</subject><subject>HCT116 Cells</subject><subject>Humans</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Phenylurea Compounds - administration & dosage</subject><subject>Pyridines - administration & dosage</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9UdtO3DAQtSpQubSf0MqPvIT6EifO4zZiAQlEtaLPlu1MSlBiL7bTsp_C3xJr2T7N6MyZM6NzEPpGySWlQv6gpJYFKTm7bNtNQUVBCCOf0CkVoi44q8TR0h84J-gsxmdCaElJ-RmdMCG55A09RW-_wjDpsMPadXhlX-YhQIc3EIeYtLOAfY9bP_oANukRtxkLOHm8cmkorq7XG3zvnbejd8s4g8Z3u8zDPwE__IVg_QTYLJCfzOAW8ccAOk3gUtbewB8fdA9uMPjfkJ5wC2l-XV4yX9Bxr8cIXz_qOfq9vnpsb4q7h-vbdnVXWC6qVLCaNZWsRF9XjDDblLI0YGRluOkE9NDZkvWsq4nVWnPWN5rRhkieLZIgan6OLva62-BfZohJTUO0MI7agZ-jolXDa9Jwwhaq2FNt8DEG6NV2756iROVUVHZcZcfVkoqiQuVUlr3vHydmM0H3f-sQA38Hhi2JLQ</recordid><startdate>20150701</startdate><enddate>20150701</enddate><creator>Napolitano, Stefania</creator><creator>Martini, Giulia</creator><creator>Rinaldi, Barbara</creator><creator>Martinelli, Erika</creator><creator>Donniacuo, Maria</creator><creator>Berrino, Liberato</creator><creator>Vitagliano, Donata</creator><creator>Morgillo, Floriana</creator><creator>Barra, Giusy</creator><creator>De Palma, Raffaele</creator><creator>Merolla, Francesco</creator><creator>Ciardiello, Fortunato</creator><creator>Troiani, Teresa</creator><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>20150701</creationdate><title>Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab</title><author>Napolitano, Stefania ; 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We have investigated the role of regorafenib, an oral multikinase inhibitor, in combination with cetuximab, an anti-EGFR mAb, to overcome anti-EGFR resistance.
We have tested, in vitro and in vivo, the effects of regorafenib in a panel of human colorectal cancer cell lines with a KRAS mutation (SW480, SW620, HCT116, LOVO, and HCT15) or with a BRAF mutation (HT29), as models of intrinsic resistance to cetuximab treatment, and in two human colorectal cancer cell lines (GEO and SW48) that are cetuximab-sensitive, as well as in their derived cells with acquired resistance to cetuximab (GEO-CR and SW48-CR).
Treatment with regorafenib determined a dose-dependent growth inhibition in all colorectal cancer cell lines. The combined treatment with cetuximab and regorafenib induced synergistic antiproliferative and apoptotic effects in cetuximab-resistant cell lines by blocking MAPK and AKT pathways. Nude mice were injected s.c. with HCT116, HCT15, GEO-CR, and SW48-CR cells. The combined treatment caused significant tumor growth inhibition. Synergistic antitumor activity of regorafenib plus cetuximab was also observed in an orthotopic colorectal cancer model of HCT116 cells. In particular, the combined treatment induced a significant tumor growth inhibition in the primary tumor site (cecum) and completely prevented metastasis formation.
The combined treatment with cetuximab and regorafenib could be a strategy to overcome resistance to anti-EGFR therapies in metastatic colorectal cancer patients.</abstract><cop>United States</cop><pmid>25838391</pmid><doi>10.1158/1078-0432.CCR-15-0020</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; American Association for Cancer Research; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection |
| subjects | Animals Antineoplastic Agents - pharmacology Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis - drug effects Cetuximab - administration & dosage Colorectal Neoplasms - drug therapy Drug Resistance, Neoplasm - drug effects Drug Synergism Female HCT116 Cells Humans Mice, Inbred BALB C Mice, Nude Phenylurea Compounds - administration & dosage Pyridines - administration & dosage Receptor, Epidermal Growth Factor - antagonists & inhibitors Xenograft Model Antitumor Assays |
| title | Primary and Acquired Resistance of Colorectal Cancer to Anti-EGFR Monoclonal Antibody Can Be Overcome by Combined Treatment of Regorafenib with Cetuximab |
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