KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy
KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the eme...
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| Veröffentlicht in: | International journal of cancer 2013-09, Vol.133 (5), p.1259-1265 |
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| creator | Valtorta, Emanuele Misale, Sandra Sartore‐Bianchi, Andrea Nagtegaal, Iris D. Paraf, François Lauricella, Calogero Dimartino, Valentina Hobor, Sebastijan Jacobs, Bart Ercolani, Cristiana Lamba, Simona Scala, Elisa Veronese, Silvio Laurent‐Puig, Pierre Siena, Salvatore Tejpar, Sabine Mottolese, Marcella Punt, Cornelis J.A. Gambacorta, Marcello Bardelli, Alberto Nicolantonio, Federica |
| description | KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti‐EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti‐EGFR treatment in a small proportion of patients.
What's new?
Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR) are one of the therapeutic options for metastatic colorectal cancer, but they are effective only in a small subset of patients. Here the authors determined the prevalence of KRAS gene amplification in a large dataset of colorectal cancer samples and assessed the possible predictive role of KRAS gene copy number status in response to anti‐EGFR treatment. The data show that amplification of the KRAS oncogene occurs in a small fraction of KRAS wild‐type cases and that KRAS amplification is causally associated with resistance to anti‐EGFR treatment. |
| doi_str_mv | 10.1002/ijc.28106 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_hal_p</sourceid><recordid>TN_cdi_hal_primary_oai_HAL_hal_00872285v1</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3074019891</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5186-29dfd5d5e378dfb39a11ffb0845b1eda8fe8fd0b682d1ff874eb278db914e8e53</originalsourceid><addsrcrecordid>eNp10d1qFDEUB_Agil2rF76ABESwF9MmmclM5nJZ-qULhaq3hkxy0mbJTKbJrLJ3PoLP6JM0666tCF4Fkh_nnJw_Qq8pOaaEsBO30sdMUFI_QTNK2qYgjPKnaJbfSNHQsj5AL1JaEUIpJ9VzdMDKilSsambo68fr-Sd8AwNg1Y_eWafV5MKA3YB18CGCnpTHWg0aIlaDwa4flZ5wJhHSGIYEeAr49Pzs-tePn5OKNzCBwdMtRDVuXqJnVvkEr_bnIfpydvp5cVEsr84vF_NloTkVdcFaYw03HMpGGNuVraLU2o6IincUjBIWhDWkqwUz-UE0FXQs066lFQjg5SE62tW9VV6O0fUqbmRQTl7Ml3J7R4hoGBP8G832_c6OMdytIU2yd0mD92qAsE6SVrTh5XZTmb79h67COg75J1mVJWU1L_9qrmNIKYJ9mIASuQ1I5oDk74CyfbOvuO56MA_yTyIZvNsDlbTyNubNu_TomqrN421HO9m5787D5v8d5eWHxa71PeRMpi4</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1433126535</pqid></control><display><type>article</type><title>KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy</title><source>MEDLINE</source><source>Wiley Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><creator>Valtorta, Emanuele ; Misale, Sandra ; Sartore‐Bianchi, Andrea ; Nagtegaal, Iris D. ; Paraf, François ; Lauricella, Calogero ; Dimartino, Valentina ; Hobor, Sebastijan ; Jacobs, Bart ; Ercolani, Cristiana ; Lamba, Simona ; Scala, Elisa ; Veronese, Silvio ; Laurent‐Puig, Pierre ; Siena, Salvatore ; Tejpar, Sabine ; Mottolese, Marcella ; Punt, Cornelis J.A. ; Gambacorta, Marcello ; Bardelli, Alberto ; Nicolantonio, Federica</creator><creatorcontrib>Valtorta, Emanuele ; Misale, Sandra ; Sartore‐Bianchi, Andrea ; Nagtegaal, Iris D. ; Paraf, François ; Lauricella, Calogero ; Dimartino, Valentina ; Hobor, Sebastijan ; Jacobs, Bart ; Ercolani, Cristiana ; Lamba, Simona ; Scala, Elisa ; Veronese, Silvio ; Laurent‐Puig, Pierre ; Siena, Salvatore ; Tejpar, Sabine ; Mottolese, Marcella ; Punt, Cornelis J.A. ; Gambacorta, Marcello ; Bardelli, Alberto ; Nicolantonio, Federica</creatorcontrib><description>KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti‐EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti‐EGFR treatment in a small proportion of patients.
What's new?
Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR) are one of the therapeutic options for metastatic colorectal cancer, but they are effective only in a small subset of patients. Here the authors determined the prevalence of KRAS gene amplification in a large dataset of colorectal cancer samples and assessed the possible predictive role of KRAS gene copy number status in response to anti‐EGFR treatment. The data show that amplification of the KRAS oncogene occurs in a small fraction of KRAS wild‐type cases and that KRAS amplification is causally associated with resistance to anti‐EGFR treatment.</description><identifier>ISSN: 0020-7136</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/ijc.28106</identifier><identifier>PMID: 23404247</identifier><identifier>CODEN: IJCNAW</identifier><language>eng</language><publisher>Hoboken, NJ: Wiley-Blackwell</publisher><subject>Biological and medical sciences ; biomarkers ; Cancer ; Cell Line, Tumor ; Cellular Biology ; cetuximab ; Colorectal cancer ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; EGFR ; EGFR therapy ; Epidermal growth factor ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Amplification ; Humans ; KRAS ; KRAS amplification ; Life Sciences ; Medical research ; Medical sciences ; Multiple tumors. Solid tumors. Tumors in childhood (general aspects) ; Mutation ; panitumumab ; Proto-Oncogene Proteins - genetics ; Proto-Oncogene Proteins p21(ras) ; ras Proteins - genetics ; Receptor, Epidermal Growth Factor - antagonists & inhibitors ; resistance ; Retrospective Studies ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Tumors</subject><ispartof>International journal of cancer, 2013-09, Vol.133 (5), p.1259-1265</ispartof><rights>Copyright © 2013 UICC</rights><rights>2014 INIST-CNRS</rights><rights>Copyright © 2013 UICC.</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5186-29dfd5d5e378dfb39a11ffb0845b1eda8fe8fd0b682d1ff874eb278db914e8e53</citedby><cites>FETCH-LOGICAL-c5186-29dfd5d5e378dfb39a11ffb0845b1eda8fe8fd0b682d1ff874eb278db914e8e53</cites><orcidid>0000-0001-8475-5459</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fijc.28106$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fijc.28106$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27491754$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23404247$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://unilim.hal.science/hal-00872285$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Valtorta, Emanuele</creatorcontrib><creatorcontrib>Misale, Sandra</creatorcontrib><creatorcontrib>Sartore‐Bianchi, Andrea</creatorcontrib><creatorcontrib>Nagtegaal, Iris D.</creatorcontrib><creatorcontrib>Paraf, François</creatorcontrib><creatorcontrib>Lauricella, Calogero</creatorcontrib><creatorcontrib>Dimartino, Valentina</creatorcontrib><creatorcontrib>Hobor, Sebastijan</creatorcontrib><creatorcontrib>Jacobs, Bart</creatorcontrib><creatorcontrib>Ercolani, Cristiana</creatorcontrib><creatorcontrib>Lamba, Simona</creatorcontrib><creatorcontrib>Scala, Elisa</creatorcontrib><creatorcontrib>Veronese, Silvio</creatorcontrib><creatorcontrib>Laurent‐Puig, Pierre</creatorcontrib><creatorcontrib>Siena, Salvatore</creatorcontrib><creatorcontrib>Tejpar, Sabine</creatorcontrib><creatorcontrib>Mottolese, Marcella</creatorcontrib><creatorcontrib>Punt, Cornelis J.A.</creatorcontrib><creatorcontrib>Gambacorta, Marcello</creatorcontrib><creatorcontrib>Bardelli, Alberto</creatorcontrib><creatorcontrib>Nicolantonio, Federica</creatorcontrib><title>KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy</title><title>International journal of cancer</title><addtitle>Int J Cancer</addtitle><description>KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti‐EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti‐EGFR treatment in a small proportion of patients.
What's new?
Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR) are one of the therapeutic options for metastatic colorectal cancer, but they are effective only in a small subset of patients. Here the authors determined the prevalence of KRAS gene amplification in a large dataset of colorectal cancer samples and assessed the possible predictive role of KRAS gene copy number status in response to anti‐EGFR treatment. The data show that amplification of the KRAS oncogene occurs in a small fraction of KRAS wild‐type cases and that KRAS amplification is causally associated with resistance to anti‐EGFR treatment.</description><subject>Biological and medical sciences</subject><subject>biomarkers</subject><subject>Cancer</subject><subject>Cell Line, Tumor</subject><subject>Cellular Biology</subject><subject>cetuximab</subject><subject>Colorectal cancer</subject><subject>Colorectal Neoplasms - drug therapy</subject><subject>Colorectal Neoplasms - genetics</subject><subject>EGFR</subject><subject>EGFR therapy</subject><subject>Epidermal growth factor</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Amplification</subject><subject>Humans</subject><subject>KRAS</subject><subject>KRAS amplification</subject><subject>Life Sciences</subject><subject>Medical research</subject><subject>Medical sciences</subject><subject>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</subject><subject>Mutation</subject><subject>panitumumab</subject><subject>Proto-Oncogene Proteins - genetics</subject><subject>Proto-Oncogene Proteins p21(ras)</subject><subject>ras Proteins - genetics</subject><subject>Receptor, Epidermal Growth Factor - antagonists & inhibitors</subject><subject>resistance</subject><subject>Retrospective Studies</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>Tumors</subject><issn>0020-7136</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp10d1qFDEUB_Agil2rF76ABESwF9MmmclM5nJZ-qULhaq3hkxy0mbJTKbJrLJ3PoLP6JM0666tCF4Fkh_nnJw_Qq8pOaaEsBO30sdMUFI_QTNK2qYgjPKnaJbfSNHQsj5AL1JaEUIpJ9VzdMDKilSsambo68fr-Sd8AwNg1Y_eWafV5MKA3YB18CGCnpTHWg0aIlaDwa4flZ5wJhHSGIYEeAr49Pzs-tePn5OKNzCBwdMtRDVuXqJnVvkEr_bnIfpydvp5cVEsr84vF_NloTkVdcFaYw03HMpGGNuVraLU2o6IincUjBIWhDWkqwUz-UE0FXQs066lFQjg5SE62tW9VV6O0fUqbmRQTl7Ml3J7R4hoGBP8G832_c6OMdytIU2yd0mD92qAsE6SVrTh5XZTmb79h67COg75J1mVJWU1L_9qrmNIKYJ9mIASuQ1I5oDk74CyfbOvuO56MA_yTyIZvNsDlbTyNubNu_TomqrN421HO9m5787D5v8d5eWHxa71PeRMpi4</recordid><startdate>20130901</startdate><enddate>20130901</enddate><creator>Valtorta, Emanuele</creator><creator>Misale, Sandra</creator><creator>Sartore‐Bianchi, Andrea</creator><creator>Nagtegaal, Iris D.</creator><creator>Paraf, François</creator><creator>Lauricella, Calogero</creator><creator>Dimartino, Valentina</creator><creator>Hobor, Sebastijan</creator><creator>Jacobs, Bart</creator><creator>Ercolani, Cristiana</creator><creator>Lamba, Simona</creator><creator>Scala, Elisa</creator><creator>Veronese, Silvio</creator><creator>Laurent‐Puig, Pierre</creator><creator>Siena, Salvatore</creator><creator>Tejpar, Sabine</creator><creator>Mottolese, Marcella</creator><creator>Punt, Cornelis J.A.</creator><creator>Gambacorta, Marcello</creator><creator>Bardelli, Alberto</creator><creator>Nicolantonio, Federica</creator><general>Wiley-Blackwell</general><general>Wiley Subscription Services, Inc</general><general>Wiley</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>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0001-8475-5459</orcidid></search><sort><creationdate>20130901</creationdate><title>KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy</title><author>Valtorta, Emanuele ; Misale, Sandra ; Sartore‐Bianchi, Andrea ; Nagtegaal, Iris D. ; Paraf, François ; Lauricella, Calogero ; Dimartino, Valentina ; Hobor, Sebastijan ; Jacobs, Bart ; Ercolani, Cristiana ; Lamba, Simona ; Scala, Elisa ; Veronese, Silvio ; Laurent‐Puig, Pierre ; Siena, Salvatore ; Tejpar, Sabine ; Mottolese, Marcella ; Punt, Cornelis J.A. ; Gambacorta, Marcello ; Bardelli, Alberto ; Nicolantonio, Federica</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5186-29dfd5d5e378dfb39a11ffb0845b1eda8fe8fd0b682d1ff874eb278db914e8e53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Biological and medical sciences</topic><topic>biomarkers</topic><topic>Cancer</topic><topic>Cell Line, Tumor</topic><topic>Cellular Biology</topic><topic>cetuximab</topic><topic>Colorectal cancer</topic><topic>Colorectal Neoplasms - drug therapy</topic><topic>Colorectal Neoplasms - genetics</topic><topic>EGFR</topic><topic>EGFR therapy</topic><topic>Epidermal growth factor</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Amplification</topic><topic>Humans</topic><topic>KRAS</topic><topic>KRAS amplification</topic><topic>Life Sciences</topic><topic>Medical research</topic><topic>Medical sciences</topic><topic>Multiple tumors. Solid tumors. Tumors in childhood (general aspects)</topic><topic>Mutation</topic><topic>panitumumab</topic><topic>Proto-Oncogene Proteins - genetics</topic><topic>Proto-Oncogene Proteins p21(ras)</topic><topic>ras Proteins - genetics</topic><topic>Receptor, Epidermal Growth Factor - antagonists & inhibitors</topic><topic>resistance</topic><topic>Retrospective Studies</topic><topic>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Valtorta, Emanuele</creatorcontrib><creatorcontrib>Misale, Sandra</creatorcontrib><creatorcontrib>Sartore‐Bianchi, Andrea</creatorcontrib><creatorcontrib>Nagtegaal, Iris D.</creatorcontrib><creatorcontrib>Paraf, François</creatorcontrib><creatorcontrib>Lauricella, Calogero</creatorcontrib><creatorcontrib>Dimartino, Valentina</creatorcontrib><creatorcontrib>Hobor, Sebastijan</creatorcontrib><creatorcontrib>Jacobs, Bart</creatorcontrib><creatorcontrib>Ercolani, Cristiana</creatorcontrib><creatorcontrib>Lamba, Simona</creatorcontrib><creatorcontrib>Scala, Elisa</creatorcontrib><creatorcontrib>Veronese, Silvio</creatorcontrib><creatorcontrib>Laurent‐Puig, Pierre</creatorcontrib><creatorcontrib>Siena, Salvatore</creatorcontrib><creatorcontrib>Tejpar, Sabine</creatorcontrib><creatorcontrib>Mottolese, Marcella</creatorcontrib><creatorcontrib>Punt, Cornelis J.A.</creatorcontrib><creatorcontrib>Gambacorta, Marcello</creatorcontrib><creatorcontrib>Bardelli, Alberto</creatorcontrib><creatorcontrib>Nicolantonio, Federica</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Valtorta, Emanuele</au><au>Misale, Sandra</au><au>Sartore‐Bianchi, Andrea</au><au>Nagtegaal, Iris D.</au><au>Paraf, François</au><au>Lauricella, Calogero</au><au>Dimartino, Valentina</au><au>Hobor, Sebastijan</au><au>Jacobs, Bart</au><au>Ercolani, Cristiana</au><au>Lamba, Simona</au><au>Scala, Elisa</au><au>Veronese, Silvio</au><au>Laurent‐Puig, Pierre</au><au>Siena, Salvatore</au><au>Tejpar, Sabine</au><au>Mottolese, Marcella</au><au>Punt, Cornelis J.A.</au><au>Gambacorta, Marcello</au><au>Bardelli, Alberto</au><au>Nicolantonio, Federica</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy</atitle><jtitle>International journal of cancer</jtitle><addtitle>Int J Cancer</addtitle><date>2013-09-01</date><risdate>2013</risdate><volume>133</volume><issue>5</issue><spage>1259</spage><epage>1265</epage><pages>1259-1265</pages><issn>0020-7136</issn><eissn>1097-0215</eissn><coden>IJCNAW</coden><abstract>KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti‐EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti‐EGFR treatment in a small proportion of patients.
What's new?
Monoclonal antibodies targeting the Epidermal Growth Factor Receptor (EGFR) are one of the therapeutic options for metastatic colorectal cancer, but they are effective only in a small subset of patients. Here the authors determined the prevalence of KRAS gene amplification in a large dataset of colorectal cancer samples and assessed the possible predictive role of KRAS gene copy number status in response to anti‐EGFR treatment. The data show that amplification of the KRAS oncogene occurs in a small fraction of KRAS wild‐type cases and that KRAS amplification is causally associated with resistance to anti‐EGFR treatment.</abstract><cop>Hoboken, NJ</cop><pub>Wiley-Blackwell</pub><pmid>23404247</pmid><doi>10.1002/ijc.28106</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-8475-5459</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of cancer, 2013-09, Vol.133 (5), p.1259-1265 |
| issn | 0020-7136 1097-0215 |
| language | eng |
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| source | MEDLINE; Wiley Journals; EZB-FREE-00999 freely available EZB journals |
| subjects | Biological and medical sciences biomarkers Cancer Cell Line, Tumor Cellular Biology cetuximab Colorectal cancer Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics EGFR EGFR therapy Epidermal growth factor Gastroenterology. Liver. Pancreas. Abdomen Gene Amplification Humans KRAS KRAS amplification Life Sciences Medical research Medical sciences Multiple tumors. Solid tumors. Tumors in childhood (general aspects) Mutation panitumumab Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins p21(ras) ras Proteins - genetics Receptor, Epidermal Growth Factor - antagonists & inhibitors resistance Retrospective Studies Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Tumors |
| title | KRAS gene amplification in colorectal cancer and impact on response to EGFR‐targeted therapy |
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