Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer.
Identifieur interne : 000706 ( Main/Exploration ); précédent : 000705; suivant : 000707Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer.
Auteurs : Riley A. Hampsch [États-Unis] ; Kevin Shee [États-Unis] ; Darcy Bates [États-Unis] ; Lionel D. Lewis [États-Unis] ; Laurent Désiré [France] ; Bertrand Leblond [France] ; Eugene Demidenko [États-Unis] ; Kurtis Stefan [États-Unis] ; Yina H. Huang [États-Unis] ; Todd W. Miller [États-Unis]Source :
- Oncotarget [ 1949-2553 ] ; 2017.
Descripteurs français
- KwdFr :
- Animaux (MeSH), Antinéoplasiques (pharmacologie), Complexe-1 cible mécanistique de la rapamycine (MeSH), Complexes multiprotéiques (métabolisme), Femelle (MeSH), Humains (MeSH), Inhibiteurs de protéines kinases (pharmacologie), MAP Kinase Kinase Kinases (métabolisme), Protéines proto-oncogènes c-akt (antagonistes et inhibiteurs), Protéines proto-oncogènes c-akt (métabolisme), Résistance aux médicaments antinéoplasiques (physiologie), Souris (MeSH), Souris SCID (MeSH), Souris de lignée NOD (MeSH), Sérine-thréonine kinases TOR (métabolisme), Tests d'activité antitumorale sur modèle de xénogreffe (MeSH), Transduction du signal (effets des médicaments et des substances chimiques), Tumeurs du sein (métabolisme).
- MESH :
- antagonistes et inhibiteurs : Protéines proto-oncogènes c-akt.
- effets des médicaments et des substances chimiques : Transduction du signal.
- métabolisme : Complexes multiprotéiques, MAP Kinase Kinase Kinases, Protéines proto-oncogènes c-akt, Sérine-thréonine kinases TOR, Tumeurs du sein.
- pharmacologie : Antinéoplasiques, Inhibiteurs de protéines kinases.
- physiologie : Résistance aux médicaments antinéoplasiques.
- Animaux, Complexe-1 cible mécanistique de la rapamycine, Femelle, Humains, Souris, Souris SCID, Souris de lignée NOD, Tests d'activité antitumorale sur modèle de xénogreffe.
English descriptors
- KwdEn :
- Animals (MeSH), Antineoplastic Agents (pharmacology), Breast Neoplasms (metabolism), Drug Resistance, Neoplasm (physiology), Female (MeSH), Humans (MeSH), MAP Kinase Kinase Kinases (metabolism), Mechanistic Target of Rapamycin Complex 1 (MeSH), Mice (MeSH), Mice, Inbred NOD (MeSH), Mice, SCID (MeSH), Multiprotein Complexes (metabolism), Protein Kinase Inhibitors (pharmacology), Proto-Oncogene Proteins c-akt (antagonists & inhibitors), Proto-Oncogene Proteins c-akt (metabolism), Signal Transduction (drug effects), TOR Serine-Threonine Kinases (metabolism), Xenograft Model Antitumor Assays (MeSH).
- MESH :
- chemical , antagonists & inhibitors : Proto-Oncogene Proteins c-akt.
- chemical , metabolism : MAP Kinase Kinase Kinases, Multiprotein Complexes, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases.
- chemical , pharmacology : Antineoplastic Agents, Protein Kinase Inhibitors.
- drug effects : Signal Transduction.
- metabolism : Breast Neoplasms.
- physiology : Drug Resistance, Neoplasm.
- Animals, Female, Humans, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Inbred NOD, Mice, SCID, Xenograft Model Antitumor Assays.
Abstract
Rac GTPases have oncogenic roles in cell growth, survival, and migration. We tested response to the Rac inhibitor EHT1864 in a panel of breast cancer cell lines. EHT1864-induced growth inhibition was associated with dual inhibition of the PI3K/AKT/mTORC1 and MEK/ERK pathways. Breast cancer cells harboring PIK3CA mutations or HER2 overexpression were most sensitive to Rac inhibition, suggesting that such oncogenic alterations link Rac activation with PI3K/AKT/mTORC1 and MEK/ERK signaling. Interestingly, EHT1864 decreased activation of the mTORC1 substrate p70S6K earlier than AKT inhibition, suggesting that Rac may activate mTORC1/p70S6K independently of AKT. Comparison of the growth-inhibitory profile of EHT1864 to 137 other anti-cancer drugs across 656 cancer cell lines revealed significant correlation with the p70S6K inhibitor PF-4708671. We confirmed that Rac complexes contain MEK1/2 and ERK1/2, but also contain p70S6K; these interactions were disrupted by EHT1864. Pharmacokinetic profiles revealed that EHT1864 was present in mouse plasma at concentrations effective in vitro for approximately 1 h after intraperitoneal administration. EHT1864 suppressed growth of HER2+ tumors, and enhanced response to anti-estrogen treatment in ER+ tumors. Further therapeutic development of Rac inhibitors for HER2+ and PIK3CA-mutant cancers is warranted.
DOI: 10.18632/oncotarget.15586
PubMed: 28423521
PubMed Central: PMC5400625
Affiliations:
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Hampsch</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation></author><author><name sortKey="Shee, Kevin" sort="Shee, Kevin" uniqKey="Shee K" first="Kevin" last="Shee">Kevin Shee</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation></author><author><name sortKey="Bates, Darcy" sort="Bates, Darcy" uniqKey="Bates D" first="Darcy" last="Bates">Darcy Bates</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation></author><author><name sortKey="Lewis, Lionel D" sort="Lewis, Lionel D" uniqKey="Lewis L" first="Lionel D" last="Lewis">Lionel D. Lewis</name><affiliation wicri:level="2"><nlm:affiliation>Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation></author><author><name sortKey="Desire, Laurent" sort="Desire, Laurent" uniqKey="Desire L" first="Laurent" last="Désiré">Laurent Désiré</name><affiliation wicri:level="3"><nlm:affiliation>Diaxonhit, 63-65 Bd. Masséna, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Diaxonhit, 63-65 Bd. Masséna, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Leblond, Bertrand" sort="Leblond, Bertrand" uniqKey="Leblond B" first="Bertrand" last="Leblond">Bertrand Leblond</name><affiliation wicri:level="3"><nlm:affiliation>Diaxonhit, 63-65 Bd. Masséna, Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Diaxonhit, 63-65 Bd. Masséna, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Demidenko, Eugene" sort="Demidenko, Eugene" uniqKey="Demidenko E" first="Eugene" last="Demidenko">Eugene Demidenko</name><affiliation wicri:level="2"><nlm:affiliation>Department of Community & Family Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Community & Family Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation></author><author><name sortKey="Stefan, Kurtis" sort="Stefan, Kurtis" uniqKey="Stefan K" first="Kurtis" last="Stefan">Kurtis Stefan</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation></author><author><name sortKey="Huang, Yina H" sort="Huang, Yina H" uniqKey="Huang Y" first="Yina H" last="Huang">Yina H. Huang</name><affiliation wicri:level="2"><nlm:affiliation>Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation></author><author><name sortKey="Miller, Todd W" sort="Miller, Todd W" uniqKey="Miller T" first="Todd W" last="Miller">Todd W. Miller</name><affiliation wicri:level="2"><nlm:affiliation>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation><affiliation wicri:level="2"><nlm:affiliation>Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH</wicri:regionArea><placeName><region type="state">New Hampshire</region></placeName></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals (MeSH)</term><term>Antineoplastic Agents (pharmacology)</term><term>Breast Neoplasms (metabolism)</term><term>Drug Resistance, Neoplasm (physiology)</term><term>Female (MeSH)</term><term>Humans (MeSH)</term><term>MAP Kinase Kinase Kinases (metabolism)</term><term>Mechanistic Target of Rapamycin Complex 1 (MeSH)</term><term>Mice (MeSH)</term><term>Mice, Inbred NOD (MeSH)</term><term>Mice, SCID (MeSH)</term><term>Multiprotein Complexes (metabolism)</term><term>Protein Kinase Inhibitors (pharmacology)</term><term>Proto-Oncogene Proteins c-akt (antagonists & inhibitors)</term><term>Proto-Oncogene Proteins c-akt (metabolism)</term><term>Signal Transduction (drug effects)</term><term>TOR Serine-Threonine Kinases (metabolism)</term><term>Xenograft Model Antitumor Assays (MeSH)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term><term>Antinéoplasiques (pharmacologie)</term><term>Complexe-1 cible mécanistique de la rapamycine (MeSH)</term><term>Complexes multiprotéiques (métabolisme)</term><term>Femelle (MeSH)</term><term>Humains (MeSH)</term><term>Inhibiteurs de protéines kinases (pharmacologie)</term><term>MAP Kinase Kinase Kinases (métabolisme)</term><term>Protéines proto-oncogènes c-akt (antagonistes et inhibiteurs)</term><term>Protéines proto-oncogènes c-akt (métabolisme)</term><term>Résistance aux médicaments antinéoplasiques (physiologie)</term><term>Souris (MeSH)</term><term>Souris SCID (MeSH)</term><term>Souris de lignée NOD (MeSH)</term><term>Sérine-thréonine kinases TOR (métabolisme)</term><term>Tests d'activité antitumorale sur modèle de xénogreffe (MeSH)</term><term>Transduction du signal (effets des médicaments et des substances chimiques)</term><term>Tumeurs du sein (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Proto-Oncogene Proteins c-akt</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>MAP Kinase Kinase Kinases</term><term>Multiprotein Complexes</term><term>Proto-Oncogene Proteins c-akt</term><term>TOR Serine-Threonine Kinases</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Agents</term><term>Protein Kinase Inhibitors</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines proto-oncogènes c-akt</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Signal Transduction</term></keywords><keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Transduction du signal</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Breast Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Complexes multiprotéiques</term><term>MAP Kinase Kinase Kinases</term><term>Protéines proto-oncogènes c-akt</term><term>Sérine-thréonine kinases TOR</term><term>Tumeurs du sein</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques</term><term>Inhibiteurs de protéines kinases</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Résistance aux médicaments antinéoplasiques</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Drug Resistance, Neoplasm</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Female</term><term>Humans</term><term>Mechanistic Target of Rapamycin Complex 1</term><term>Mice</term><term>Mice, Inbred NOD</term><term>Mice, SCID</term><term>Xenograft Model Antitumor Assays</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Complexe-1 cible mécanistique de la rapamycine</term><term>Femelle</term><term>Humains</term><term>Souris</term><term>Souris SCID</term><term>Souris de lignée NOD</term><term>Tests d'activité antitumorale sur modèle de xénogreffe</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Rac GTPases have oncogenic roles in cell growth, survival, and migration. We tested response to the Rac inhibitor EHT1864 in a panel of breast cancer cell lines. EHT1864-induced growth inhibition was associated with dual inhibition of the PI3K/AKT/mTORC1 and MEK/ERK pathways. Breast cancer cells harboring PIK3CA mutations or HER2 overexpression were most sensitive to Rac inhibition, suggesting that such oncogenic alterations link Rac activation with PI3K/AKT/mTORC1 and MEK/ERK signaling. Interestingly, EHT1864 decreased activation of the mTORC1 substrate p70S6K earlier than AKT inhibition, suggesting that Rac may activate mTORC1/p70S6K independently of AKT. Comparison of the growth-inhibitory profile of EHT1864 to 137 other anti-cancer drugs across 656 cancer cell lines revealed significant correlation with the p70S6K inhibitor PF-4708671. We confirmed that Rac complexes contain MEK1/2 and ERK1/2, but also contain p70S6K; these interactions were disrupted by EHT1864. Pharmacokinetic profiles revealed that EHT1864 was present in mouse plasma at concentrations effective in vitro for approximately 1 h after intraperitoneal administration. EHT1864 suppressed growth of HER2+ tumors, and enhanced response to anti-estrogen treatment in ER+ tumors. Further therapeutic development of Rac inhibitors for HER2+ and PIK3CA-mutant cancers is warranted.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28423521</PMID><DateCompleted><Year>2017</Year><Month>10</Month><Day>10</Day></DateCompleted><DateRevised><Year>2018</Year><Month>11</Month><Day>13</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1949-2553</ISSN><JournalIssue CitedMedium="Internet"><Volume>8</Volume><Issue>13</Issue><PubDate><Year>2017</Year><Month>Mar</Month><Day>28</Day></PubDate></JournalIssue><Title>Oncotarget</Title><ISOAbbreviation>Oncotarget</ISOAbbreviation></Journal><ArticleTitle>Therapeutic sensitivity to Rac GTPase inhibition requires consequential suppression of mTORC1, AKT, and MEK signaling in breast cancer.</ArticleTitle><Pagination><MedlinePgn>21806-21817</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.18632/oncotarget.15586</ELocationID><Abstract><AbstractText>Rac GTPases have oncogenic roles in cell growth, survival, and migration. We tested response to the Rac inhibitor EHT1864 in a panel of breast cancer cell lines. EHT1864-induced growth inhibition was associated with dual inhibition of the PI3K/AKT/mTORC1 and MEK/ERK pathways. Breast cancer cells harboring PIK3CA mutations or HER2 overexpression were most sensitive to Rac inhibition, suggesting that such oncogenic alterations link Rac activation with PI3K/AKT/mTORC1 and MEK/ERK signaling. Interestingly, EHT1864 decreased activation of the mTORC1 substrate p70S6K earlier than AKT inhibition, suggesting that Rac may activate mTORC1/p70S6K independently of AKT. Comparison of the growth-inhibitory profile of EHT1864 to 137 other anti-cancer drugs across 656 cancer cell lines revealed significant correlation with the p70S6K inhibitor PF-4708671. We confirmed that Rac complexes contain MEK1/2 and ERK1/2, but also contain p70S6K; these interactions were disrupted by EHT1864. Pharmacokinetic profiles revealed that EHT1864 was present in mouse plasma at concentrations effective in vitro for approximately 1 h after intraperitoneal administration. EHT1864 suppressed growth of HER2+ tumors, and enhanced response to anti-estrogen treatment in ER+ tumors. Further therapeutic development of Rac inhibitors for HER2+ and PIK3CA-mutant cancers is warranted.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Hampsch</LastName><ForeName>Riley A</ForeName><Initials>RA</Initials><AffiliationInfo><Affiliation>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Shee</LastName><ForeName>Kevin</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Department of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bates</LastName><ForeName>Darcy</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lewis</LastName><ForeName>Lionel D</ForeName><Initials>LD</Initials><AffiliationInfo><Affiliation>Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Désiré</LastName><ForeName>Laurent</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Diaxonhit, 63-65 Bd. Masséna, Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Leblond</LastName><ForeName>Bertrand</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Diaxonhit, 63-65 Bd. 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