Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations
Background Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in KRAS mutant colon cancer but are met with significant resistance. Clinical investigations have demons...
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| Veröffentlicht in: | British journal of cancer 2019-04, Vol.120 (9), p.941-951 |
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| creator | Moon, Jai-Hee Hong, Seung-Woo Kim, Jeong Eun Shin, Jae-Sik Kim, Jin-Sun Jung, Soo-A Ha, Seung Hee Lee, Seul Kim, Joseph Lee, Dae Hee Park, Yoon Sun Kim, Dong Min Park, Sang-Soo Hong, Jun Ki Kim, Do Yeon Kim, Eun Ho Jung, Joonyee Kim, Mi Jin Kim, Seung-Mi Deming, Dustin A. Kim, Kyunggon Kim, Tae Won Jin, Dong-Hoon |
| description | Background
Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in
KRAS
mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients.
Methods
We investigated a biomarker of response for MEK inhibition in
KRAS
mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in
PIK3CA
wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo.
Results
We identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in β-catenin in
PIK3CA
wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing
PIK3CA
wt.
Conclusions
We propose that inhibition of the WNT pathway, particularly β-catenin, may bypass resistance to MEK inhibition in human
PIK3CA
mt colon cancer. Therefore, we suggest that β-catenin is a potential predictive marker of MEK inhibitor resistance. |
| doi_str_mv | 10.1038/s41416-019-0434-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6734664</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2217460089</sourcerecordid><originalsourceid>FETCH-LOGICAL-c470t-81a1b8f3c5335328400efe7761a58b2b33148bba78f62c99158f453de6c18df03</originalsourceid><addsrcrecordid>eNp1kc9u1DAQxi1ERZfCA3BBlrj0YhjHju1ckFarAtW2AkE5W47XybpK7GInRX2tPkifqV5tKX8kTtbM_OYbf_oQekXhLQWm3mVOORUEaEOAM07qJ2hBa1YRqir5FC0AQBJoKjhEz3O-LGUDSj5DhwwaznktF6i_MKl3kw89vrsl1kwu-IDjtUs2ji7j85M19mHrWz_5GHBy2efJBOtKF9s4lJ7dlQn_9NMWr78uv2ETNvjL6ZqtlnicJ7NbzC_QQWeG7F4-vEfo-4eTi9Uncvb54-lqeUYslzARRQ1tVcdszVgxojiA65yUgppatVXLGOWqbY1Unahs09BadbxmGycsVZsO2BF6v9e9mtvRbawLUzKDvkp-NOlGR-P135Pgt7qP11pIxoXgReD4QSDFH7PLkx59tm4YTHBxzrqqgFFWC8EK-uYf9DLOKRR7haKSCwDVFIruKZtizsl1j5-hoHcx6n2MusSodzHquuy8_tPF48av3ApQ7YFcRqF36ffp_6veA3P9qEk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2217460089</pqid></control><display><type>article</type><title>Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations</title><source>MEDLINE</source><source>SpringerLink Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Moon, Jai-Hee ; Hong, Seung-Woo ; Kim, Jeong Eun ; Shin, Jae-Sik ; Kim, Jin-Sun ; Jung, Soo-A ; Ha, Seung Hee ; Lee, Seul ; Kim, Joseph ; Lee, Dae Hee ; Park, Yoon Sun ; Kim, Dong Min ; Park, Sang-Soo ; Hong, Jun Ki ; Kim, Do Yeon ; Kim, Eun Ho ; Jung, Joonyee ; Kim, Mi Jin ; Kim, Seung-Mi ; Deming, Dustin A. ; Kim, Kyunggon ; Kim, Tae Won ; Jin, Dong-Hoon</creator><creatorcontrib>Moon, Jai-Hee ; Hong, Seung-Woo ; Kim, Jeong Eun ; Shin, Jae-Sik ; Kim, Jin-Sun ; Jung, Soo-A ; Ha, Seung Hee ; Lee, Seul ; Kim, Joseph ; Lee, Dae Hee ; Park, Yoon Sun ; Kim, Dong Min ; Park, Sang-Soo ; Hong, Jun Ki ; Kim, Do Yeon ; Kim, Eun Ho ; Jung, Joonyee ; Kim, Mi Jin ; Kim, Seung-Mi ; Deming, Dustin A. ; Kim, Kyunggon ; Kim, Tae Won ; Jin, Dong-Hoon</creatorcontrib><description>Background
Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in
KRAS
mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients.
Methods
We investigated a biomarker of response for MEK inhibition in
KRAS
mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in
PIK3CA
wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo.
Results
We identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in β-catenin in
PIK3CA
wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing
PIK3CA
wt.
Conclusions
We propose that inhibition of the WNT pathway, particularly β-catenin, may bypass resistance to MEK inhibition in human
PIK3CA
mt colon cancer. Therefore, we suggest that β-catenin is a potential predictive marker of MEK inhibitor resistance.</description><identifier>ISSN: 0007-0920</identifier><identifier>EISSN: 1532-1827</identifier><identifier>DOI: 10.1038/s41416-019-0434-5</identifier><identifier>PMID: 30944457</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1059/2326 ; 631/67/1504/1885/1393 ; 631/67/1857 ; Acetamides - pharmacology ; Animals ; beta Catenin - antagonists & inhibitors ; beta Catenin - metabolism ; Biomarkers, Pharmacological - metabolism ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Class I Phosphatidylinositol 3-Kinases - genetics ; Class I Phosphatidylinositol 3-Kinases - metabolism ; Colon cancer ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - genetics ; Colonic Neoplasms - metabolism ; Colorectal cancer ; Drug Resistance ; Drug Resistance, Viral ; Epidemiology ; Humans ; Inhibition ; K-Ras protein ; Kinases ; MAP Kinase Kinase 1 - antagonists & inhibitors ; MAP Kinase Kinase 1 - metabolism ; MAP Kinase Kinase 3 - antagonists & inhibitors ; MAP Kinase Kinase 3 - metabolism ; MEK inhibitors ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Medicine ; Oncology ; Protein Kinase Inhibitors - pharmacology ; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors ; Proto-Oncogene Proteins p21(ras) - genetics ; Proto-Oncogene Proteins p21(ras) - metabolism ; Pyrimidinones - pharmacology ; Regression analysis ; Signal transduction ; Tumors ; Wnt protein ; Xenograft Model Antitumor Assays ; Xenografts ; β-Catenin</subject><ispartof>British journal of cancer, 2019-04, Vol.120 (9), p.941-951</ispartof><rights>Cancer Research UK 2019</rights><rights>Cancer Research UK 2019.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-81a1b8f3c5335328400efe7761a58b2b33148bba78f62c99158f453de6c18df03</citedby><cites>FETCH-LOGICAL-c470t-81a1b8f3c5335328400efe7761a58b2b33148bba78f62c99158f453de6c18df03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734664/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734664/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41464,42533,51294,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30944457$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moon, Jai-Hee</creatorcontrib><creatorcontrib>Hong, Seung-Woo</creatorcontrib><creatorcontrib>Kim, Jeong Eun</creatorcontrib><creatorcontrib>Shin, Jae-Sik</creatorcontrib><creatorcontrib>Kim, Jin-Sun</creatorcontrib><creatorcontrib>Jung, Soo-A</creatorcontrib><creatorcontrib>Ha, Seung Hee</creatorcontrib><creatorcontrib>Lee, Seul</creatorcontrib><creatorcontrib>Kim, Joseph</creatorcontrib><creatorcontrib>Lee, Dae Hee</creatorcontrib><creatorcontrib>Park, Yoon Sun</creatorcontrib><creatorcontrib>Kim, Dong Min</creatorcontrib><creatorcontrib>Park, Sang-Soo</creatorcontrib><creatorcontrib>Hong, Jun Ki</creatorcontrib><creatorcontrib>Kim, Do Yeon</creatorcontrib><creatorcontrib>Kim, Eun Ho</creatorcontrib><creatorcontrib>Jung, Joonyee</creatorcontrib><creatorcontrib>Kim, Mi Jin</creatorcontrib><creatorcontrib>Kim, Seung-Mi</creatorcontrib><creatorcontrib>Deming, Dustin A.</creatorcontrib><creatorcontrib>Kim, Kyunggon</creatorcontrib><creatorcontrib>Kim, Tae Won</creatorcontrib><creatorcontrib>Jin, Dong-Hoon</creatorcontrib><title>Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations</title><title>British journal of cancer</title><addtitle>Br J Cancer</addtitle><addtitle>Br J Cancer</addtitle><description>Background
Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in
KRAS
mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients.
Methods
We investigated a biomarker of response for MEK inhibition in
KRAS
mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in
PIK3CA
wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo.
Results
We identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in β-catenin in
PIK3CA
wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing
PIK3CA
wt.
Conclusions
We propose that inhibition of the WNT pathway, particularly β-catenin, may bypass resistance to MEK inhibition in human
PIK3CA
mt colon cancer. Therefore, we suggest that β-catenin is a potential predictive marker of MEK inhibitor resistance.</description><subject>631/67/1059/2326</subject><subject>631/67/1504/1885/1393</subject><subject>631/67/1857</subject><subject>Acetamides - pharmacology</subject><subject>Animals</subject><subject>beta Catenin - antagonists & inhibitors</subject><subject>beta Catenin - metabolism</subject><subject>Biomarkers, Pharmacological - metabolism</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Class I Phosphatidylinositol 3-Kinases - genetics</subject><subject>Class I Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - drug therapy</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colorectal cancer</subject><subject>Drug Resistance</subject><subject>Drug Resistance, Viral</subject><subject>Epidemiology</subject><subject>Humans</subject><subject>Inhibition</subject><subject>K-Ras protein</subject><subject>Kinases</subject><subject>MAP Kinase Kinase 1 - antagonists & inhibitors</subject><subject>MAP Kinase Kinase 1 - metabolism</subject><subject>MAP Kinase Kinase 3 - antagonists & inhibitors</subject><subject>MAP Kinase Kinase 3 - metabolism</subject><subject>MEK inhibitors</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Molecular Medicine</subject><subject>Oncology</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins p21(ras) - genetics</subject><subject>Proto-Oncogene Proteins p21(ras) - metabolism</subject><subject>Pyrimidinones - pharmacology</subject><subject>Regression analysis</subject><subject>Signal transduction</subject><subject>Tumors</subject><subject>Wnt protein</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><subject>β-Catenin</subject><issn>0007-0920</issn><issn>1532-1827</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc9u1DAQxi1ERZfCA3BBlrj0YhjHju1ckFarAtW2AkE5W47XybpK7GInRX2tPkifqV5tKX8kTtbM_OYbf_oQekXhLQWm3mVOORUEaEOAM07qJ2hBa1YRqir5FC0AQBJoKjhEz3O-LGUDSj5DhwwaznktF6i_MKl3kw89vrsl1kwu-IDjtUs2ji7j85M19mHrWz_5GHBy2efJBOtKF9s4lJ7dlQn_9NMWr78uv2ETNvjL6ZqtlnicJ7NbzC_QQWeG7F4-vEfo-4eTi9Uncvb54-lqeUYslzARRQ1tVcdszVgxojiA65yUgppatVXLGOWqbY1Unahs09BadbxmGycsVZsO2BF6v9e9mtvRbawLUzKDvkp-NOlGR-P135Pgt7qP11pIxoXgReD4QSDFH7PLkx59tm4YTHBxzrqqgFFWC8EK-uYf9DLOKRR7haKSCwDVFIruKZtizsl1j5-hoHcx6n2MusSodzHquuy8_tPF48av3ApQ7YFcRqF36ffp_6veA3P9qEk</recordid><startdate>20190430</startdate><enddate>20190430</enddate><creator>Moon, Jai-Hee</creator><creator>Hong, Seung-Woo</creator><creator>Kim, Jeong Eun</creator><creator>Shin, Jae-Sik</creator><creator>Kim, Jin-Sun</creator><creator>Jung, Soo-A</creator><creator>Ha, Seung Hee</creator><creator>Lee, Seul</creator><creator>Kim, Joseph</creator><creator>Lee, Dae Hee</creator><creator>Park, Yoon Sun</creator><creator>Kim, Dong Min</creator><creator>Park, Sang-Soo</creator><creator>Hong, Jun Ki</creator><creator>Kim, Do Yeon</creator><creator>Kim, Eun Ho</creator><creator>Jung, Joonyee</creator><creator>Kim, Mi Jin</creator><creator>Kim, Seung-Mi</creator><creator>Deming, Dustin A.</creator><creator>Kim, Kyunggon</creator><creator>Kim, Tae Won</creator><creator>Jin, Dong-Hoon</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190430</creationdate><title>Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations</title><author>Moon, Jai-Hee ; Hong, Seung-Woo ; Kim, Jeong Eun ; Shin, Jae-Sik ; Kim, Jin-Sun ; Jung, Soo-A ; Ha, Seung Hee ; Lee, Seul ; Kim, Joseph ; Lee, Dae Hee ; Park, Yoon Sun ; Kim, Dong Min ; Park, Sang-Soo ; Hong, Jun Ki ; Kim, Do Yeon ; Kim, Eun Ho ; Jung, Joonyee ; Kim, Mi Jin ; Kim, Seung-Mi ; Deming, Dustin A. ; Kim, Kyunggon ; Kim, Tae Won ; Jin, Dong-Hoon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-81a1b8f3c5335328400efe7761a58b2b33148bba78f62c99158f453de6c18df03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>631/67/1059/2326</topic><topic>631/67/1504/1885/1393</topic><topic>631/67/1857</topic><topic>Acetamides - pharmacology</topic><topic>Animals</topic><topic>beta Catenin - antagonists & inhibitors</topic><topic>beta Catenin - metabolism</topic><topic>Biomarkers, Pharmacological - metabolism</topic><topic>Biomarkers, Tumor - genetics</topic><topic>Biomarkers, Tumor - metabolism</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors</topic><topic>Class I Phosphatidylinositol 3-Kinases - genetics</topic><topic>Class I Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Colon cancer</topic><topic>Colonic Neoplasms - drug therapy</topic><topic>Colonic Neoplasms - genetics</topic><topic>Colonic Neoplasms - metabolism</topic><topic>Colorectal cancer</topic><topic>Drug Resistance</topic><topic>Drug Resistance, Viral</topic><topic>Epidemiology</topic><topic>Humans</topic><topic>Inhibition</topic><topic>K-Ras protein</topic><topic>Kinases</topic><topic>MAP Kinase Kinase 1 - antagonists & inhibitors</topic><topic>MAP Kinase Kinase 1 - metabolism</topic><topic>MAP Kinase Kinase 3 - antagonists & inhibitors</topic><topic>MAP Kinase Kinase 3 - metabolism</topic><topic>MEK inhibitors</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Molecular Medicine</topic><topic>Oncology</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins p21(ras) - genetics</topic><topic>Proto-Oncogene Proteins p21(ras) - metabolism</topic><topic>Pyrimidinones - pharmacology</topic><topic>Regression analysis</topic><topic>Signal transduction</topic><topic>Tumors</topic><topic>Wnt protein</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><topic>β-Catenin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Moon, Jai-Hee</creatorcontrib><creatorcontrib>Hong, Seung-Woo</creatorcontrib><creatorcontrib>Kim, Jeong Eun</creatorcontrib><creatorcontrib>Shin, Jae-Sik</creatorcontrib><creatorcontrib>Kim, Jin-Sun</creatorcontrib><creatorcontrib>Jung, Soo-A</creatorcontrib><creatorcontrib>Ha, Seung Hee</creatorcontrib><creatorcontrib>Lee, Seul</creatorcontrib><creatorcontrib>Kim, Joseph</creatorcontrib><creatorcontrib>Lee, Dae Hee</creatorcontrib><creatorcontrib>Park, Yoon Sun</creatorcontrib><creatorcontrib>Kim, Dong Min</creatorcontrib><creatorcontrib>Park, Sang-Soo</creatorcontrib><creatorcontrib>Hong, Jun Ki</creatorcontrib><creatorcontrib>Kim, Do Yeon</creatorcontrib><creatorcontrib>Kim, Eun Ho</creatorcontrib><creatorcontrib>Jung, Joonyee</creatorcontrib><creatorcontrib>Kim, Mi Jin</creatorcontrib><creatorcontrib>Kim, Seung-Mi</creatorcontrib><creatorcontrib>Deming, Dustin A.</creatorcontrib><creatorcontrib>Kim, Kyunggon</creatorcontrib><creatorcontrib>Kim, Tae Won</creatorcontrib><creatorcontrib>Jin, Dong-Hoon</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>British Nursing Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>British journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Moon, Jai-Hee</au><au>Hong, Seung-Woo</au><au>Kim, Jeong Eun</au><au>Shin, Jae-Sik</au><au>Kim, Jin-Sun</au><au>Jung, Soo-A</au><au>Ha, Seung Hee</au><au>Lee, Seul</au><au>Kim, Joseph</au><au>Lee, Dae Hee</au><au>Park, Yoon Sun</au><au>Kim, Dong Min</au><au>Park, Sang-Soo</au><au>Hong, Jun Ki</au><au>Kim, Do Yeon</au><au>Kim, Eun Ho</au><au>Jung, Joonyee</au><au>Kim, Mi Jin</au><au>Kim, Seung-Mi</au><au>Deming, Dustin A.</au><au>Kim, Kyunggon</au><au>Kim, Tae Won</au><au>Jin, Dong-Hoon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations</atitle><jtitle>British journal of cancer</jtitle><stitle>Br J Cancer</stitle><addtitle>Br J Cancer</addtitle><date>2019-04-30</date><risdate>2019</risdate><volume>120</volume><issue>9</issue><spage>941</spage><epage>951</epage><pages>941-951</pages><issn>0007-0920</issn><eissn>1532-1827</eissn><abstract>Background
Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signalling pathway and are attractive targets for cancer therapy. These agents continue to be investigated in
KRAS
mutant colon cancer but are met with significant resistance. Clinical investigations have demonstrated that these strategies are not well tolerated by patients.
Methods
We investigated a biomarker of response for MEK inhibition in
KRAS
mutant colon cancers by LC-MS/MS analysis. We tested the MEK inhibitor in
PIK3CA
wild(wt) and mutant(mt) colon cancer cells. In addition, we tested the combinational effects of MEK and TNKS inhibitor in vitro and in vivo.
Results
We identified β-catenin, a key mediator of the WNT pathway, in response to MEK inhibitor. MEK inhibition led to a decrease in β-catenin in
PIK3CA
wt colon cancer cells but not in mt. Tumour regression was promoted by combination of MEK inhibition and NVP-TNS656, which targets the WNT pathway. Furthermore, inhibition of MEK promoted tumour regression in colon cancer patient-derived xenograft models expressing
PIK3CA
wt.
Conclusions
We propose that inhibition of the WNT pathway, particularly β-catenin, may bypass resistance to MEK inhibition in human
PIK3CA
mt colon cancer. Therefore, we suggest that β-catenin is a potential predictive marker of MEK inhibitor resistance.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30944457</pmid><doi>10.1038/s41416-019-0434-5</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0007-0920 |
| ispartof | British journal of cancer, 2019-04, Vol.120 (9), p.941-951 |
| issn | 0007-0920 1532-1827 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6734664 |
| source | MEDLINE; SpringerLink Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | 631/67/1059/2326 631/67/1504/1885/1393 631/67/1857 Acetamides - pharmacology Animals beta Catenin - antagonists & inhibitors beta Catenin - metabolism Biomarkers, Pharmacological - metabolism Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Biomedical and Life Sciences Biomedicine Cancer Research Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors Class I Phosphatidylinositol 3-Kinases - genetics Class I Phosphatidylinositol 3-Kinases - metabolism Colon cancer Colonic Neoplasms - drug therapy Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Colorectal cancer Drug Resistance Drug Resistance, Viral Epidemiology Humans Inhibition K-Ras protein Kinases MAP Kinase Kinase 1 - antagonists & inhibitors MAP Kinase Kinase 1 - metabolism MAP Kinase Kinase 3 - antagonists & inhibitors MAP Kinase Kinase 3 - metabolism MEK inhibitors Mice Mice, Inbred BALB C Mice, Nude Molecular Medicine Oncology Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors Proto-Oncogene Proteins p21(ras) - genetics Proto-Oncogene Proteins p21(ras) - metabolism Pyrimidinones - pharmacology Regression analysis Signal transduction Tumors Wnt protein Xenograft Model Antitumor Assays Xenografts β-Catenin |
| title | Targeting β-catenin overcomes MEK inhibition resistance in colon cancer with KRAS and PIK3CA mutations |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T05%3A17%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20%CE%B2-catenin%20overcomes%20MEK%20inhibition%20resistance%20in%20colon%20cancer%20with%20KRAS%20and%20PIK3CA%20mutations&rft.jtitle=British%20journal%20of%20cancer&rft.au=Moon,%20Jai-Hee&rft.date=2019-04-30&rft.volume=120&rft.issue=9&rft.spage=941&rft.epage=951&rft.pages=941-951&rft.issn=0007-0920&rft.eissn=1532-1827&rft_id=info:doi/10.1038/s41416-019-0434-5&rft_dat=%3Cproquest_pubme%3E2217460089%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2217460089&rft_id=info:pmid/30944457&rfr_iscdi=true |