Akt targeting as a strategy to boost chemotherapy efficacy in non-small cell lung cancer through metabolism suppression
Identifieur interne : 001213 ( Main/Exploration ); précédent : 001212; suivant : 001214Akt targeting as a strategy to boost chemotherapy efficacy in non-small cell lung cancer through metabolism suppression
Auteurs : Marion Le Grand [France, Australie] ; Raphael Berges [France] ; Eddy Pasquier [France] ; Marie-Pierre Montero [France] ; Laurence Borge [France] ; Alice Carrier [France] ; Sophie Vasseur [France] ; Veronique Bourgarel [France] ; Duje Buric [France] ; Nicolas André [France] ; Diane Braguer [France] ; Manon Carré [France]Source :
- Scientific Reports [ 2045-2322 ] ; 2017.
Abstract
Metabolic reprogramming is a hallmark of cancer development, mediated by genetic and epigenetic alterations that may be pharmacologically targeted. Among oncogenes, the kinase Akt is commonly overexpressed in tumors and favors glycolysis, providing a rationale for using Akt inhibitors. Here, we addressed the question of whether and how inhibiting Akt activity could improve therapy of non-small cell lung cancer (NSCLC) that represents more than 80% of all lung cancer cases. First, we demonstrated that Akt inhibitors interacted synergistically with Microtubule-Targeting Agents (MTAs) and specifically in cancer cell lines, including those resistant to chemotherapy agents and anti-EGFR targeted therapies.
Url:
DOI: 10.1038/srep45136
PubMed: 28332584
PubMed Central: 5362809
Affiliations:
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sort="Le Grand, Marion" uniqKey="Le Grand M" first="Marion" last="Le Grand">Marion Le Grand</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Children’s Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales</institution>, Randwick, NSW,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Berges, Raphael" sort="Berges, Raphael" uniqKey="Berges R" first="Raphael" last="Berges">Raphael Berges</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Pasquier, Eddy" sort="Pasquier, Eddy" uniqKey="Pasquier E" first="Eddy" last="Pasquier">Eddy Pasquier</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Metronomics Global Health Initiative</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Montero, Marie Pierre" sort="Montero, Marie Pierre" uniqKey="Montero M" first="Marie-Pierre" last="Montero">Marie-Pierre Montero</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Borge, Laurence" sort="Borge, Laurence" uniqKey="Borge L" first="Laurence" last="Borge">Laurence Borge</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, Inserm U1068, Institut Paoli-Calmettes</institution>, 13009 Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Carrier, Alice" sort="Carrier, Alice" uniqKey="Carrier A" first="Alice" last="Carrier">Alice Carrier</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, Inserm U1068, Institut Paoli-Calmettes</institution>, 13009 Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vasseur, Sophie" sort="Vasseur, Sophie" uniqKey="Vasseur S" first="Sophie" last="Vasseur">Sophie Vasseur</name><affiliation wicri:level="1"><nlm:aff id="a4"><institution>Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, Inserm U1068, Institut Paoli-Calmettes</institution>, 13009 Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Bourgarel, Veronique" sort="Bourgarel, Veronique" uniqKey="Bourgarel V" first="Veronique" last="Bourgarel">Veronique Bourgarel</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Assistance Publique – Hopitaux de Marseille (AP-HM)</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Buric, Duje" sort="Buric, Duje" uniqKey="Buric D" first="Duje" last="Buric">Duje Buric</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Andre, Nicolas" sort="Andre, Nicolas" uniqKey="Andre N" first="Nicolas" last="André">Nicolas André</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a3"><institution>Metronomics Global Health Initiative</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a6"><institution>Service d’Hématologie & Oncologie Pédiatrique</institution>, AP-HM, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Braguer, Diane" sort="Braguer, Diane" uniqKey="Braguer D" first="Diane" last="Braguer">Diane Braguer</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a5"><institution>Assistance Publique – Hopitaux de Marseille (AP-HM)</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Carre, Manon" sort="Carre, Manon" uniqKey="Carre M" first="Manon" last="Carré">Manon Carré</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie</institution>, Marseille,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific Reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Metabolic reprogramming is a hallmark of cancer development, mediated by genetic and epigenetic alterations that may be pharmacologically targeted. Among oncogenes, the kinase Akt is commonly overexpressed in tumors and favors glycolysis, providing a rationale for using Akt inhibitors. Here, we addressed the question of whether and how inhibiting Akt activity could improve therapy of non-small cell lung cancer (NSCLC) that represents more than 80% of all lung cancer cases. First, we demonstrated that Akt inhibitors interacted synergistically with Microtubule-Targeting Agents (MTAs) and specifically in cancer cell lines, including those resistant to chemotherapy agents and anti-EGFR targeted therapies. <italic>In vivo</italic>, we further revealed that the chronic administration of low-doses of paclitaxel - <italic>i.e</italic>. metronomic scheduling - and the anti-Akt perifosine was the most efficient and the best tolerated treatment against NSCLC. Regarding drug mechanism of action, perifosine potentiated the pro-apoptotic effects of paclitaxel, independently of cell cycle arrest, and combining paclitaxel/perifosine resulted in a sustained suppression of glycolytic and mitochondrial metabolism. This study points out that targeting cancer cell bioenergetics may represent a novel therapeutic avenue in NSCLC, and provides a strong foundation for future clinical trials of metronomic MTAs combined with Akt inhibitors.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Torre, L A" uniqKey="Torre L">L. A. Torre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aisner, D L" uniqKey="Aisner D">D. L. Aisner</name></author><author><name sortKey="Marshall, C B" uniqKey="Marshall C">C. B. Marshall</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peters, S" uniqKey="Peters S">S. 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Pouysségur</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Caino, M C" uniqKey="Caino M">M. C. Caino</name></author><author><name sortKey="Altieri, D C" uniqKey="Altieri D">D. C. Altieri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pasquier, E" uniqKey="Pasquier E">E. Pasquier</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Australie</li><li>France</li></country></list><tree><country name="France"><noRegion><name sortKey="Le Grand, Marion" sort="Le Grand, Marion" uniqKey="Le Grand M" first="Marion" last="Le Grand">Marion Le Grand</name></noRegion><name sortKey="Andre, Nicolas" sort="Andre, Nicolas" uniqKey="Andre N" first="Nicolas" last="André">Nicolas André</name><name sortKey="Andre, Nicolas" sort="Andre, Nicolas" uniqKey="Andre N" first="Nicolas" last="André">Nicolas André</name><name sortKey="Andre, Nicolas" sort="Andre, Nicolas" uniqKey="Andre N" first="Nicolas" last="André">Nicolas André</name><name sortKey="Berges, Raphael" sort="Berges, Raphael" uniqKey="Berges R" first="Raphael" last="Berges">Raphael Berges</name><name sortKey="Borge, Laurence" sort="Borge, Laurence" uniqKey="Borge L" first="Laurence" last="Borge">Laurence Borge</name><name sortKey="Bourgarel, Veronique" sort="Bourgarel, Veronique" uniqKey="Bourgarel V" first="Veronique" last="Bourgarel">Veronique Bourgarel</name><name sortKey="Bourgarel, Veronique" sort="Bourgarel, Veronique" uniqKey="Bourgarel V" first="Veronique" last="Bourgarel">Veronique Bourgarel</name><name sortKey="Braguer, Diane" sort="Braguer, Diane" uniqKey="Braguer D" first="Diane" last="Braguer">Diane Braguer</name><name sortKey="Braguer, Diane" sort="Braguer, Diane" uniqKey="Braguer D" first="Diane" last="Braguer">Diane Braguer</name><name sortKey="Buric, Duje" sort="Buric, Duje" uniqKey="Buric D" first="Duje" last="Buric">Duje Buric</name><name sortKey="Carre, Manon" sort="Carre, Manon" uniqKey="Carre M" first="Manon" last="Carré">Manon Carré</name><name sortKey="Carrier, Alice" sort="Carrier, Alice" uniqKey="Carrier A" first="Alice" last="Carrier">Alice Carrier</name><name sortKey="Montero, Marie Pierre" sort="Montero, Marie Pierre" uniqKey="Montero M" first="Marie-Pierre" last="Montero">Marie-Pierre Montero</name><name sortKey="Pasquier, Eddy" sort="Pasquier, Eddy" uniqKey="Pasquier E" first="Eddy" last="Pasquier">Eddy Pasquier</name><name sortKey="Pasquier, Eddy" sort="Pasquier, Eddy" uniqKey="Pasquier E" first="Eddy" last="Pasquier">Eddy Pasquier</name><name sortKey="Vasseur, Sophie" sort="Vasseur, Sophie" uniqKey="Vasseur S" first="Sophie" last="Vasseur">Sophie Vasseur</name></country><country name="Australie"><noRegion><name sortKey="Le Grand, Marion" sort="Le Grand, Marion" uniqKey="Le Grand M" first="Marion" last="Le Grand">Marion Le Grand</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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