Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase
Cancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mech...
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| Veröffentlicht in: | Molecular cancer therapeutics 2018-12, Vol.17 (12), p.2710-2721 |
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| container_title | Molecular cancer therapeutics |
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| creator | Song, Jin H Singh, Neha Luevano, Libia A Padi, Sathish K R Okumura, Koichi Olive, Virginie Black, Stephen M Warfel, Noel A Goodrich, David W Kraft, Andrew S |
| description | Cancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element activity. PIM prevents cell death induced by PI3K-AKT-inhibitory drugs through a noncanonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity. Importantly, PIM also controls NAD(P)H production by increasing glucose flux through the pentose phosphate shunt decreasing ROS production, and thereby diminishing the cytotoxicity of PI3K-AKT inhibitors. Treatment with PIM kinase inhibitors reverses this resistance phenotype, making tumors increasingly susceptible to small-molecule therapeutics, which block the PI3K-AKT pathway. |
| doi_str_mv | 10.1158/1535-7163.MCT-18-0374 |
| format | Article |
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However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element activity. PIM prevents cell death induced by PI3K-AKT-inhibitory drugs through a noncanonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity. Importantly, PIM also controls NAD(P)H production by increasing glucose flux through the pentose phosphate shunt decreasing ROS production, and thereby diminishing the cytotoxicity of PI3K-AKT inhibitors. Treatment with PIM kinase inhibitors reverses this resistance phenotype, making tumors increasingly susceptible to small-molecule therapeutics, which block the PI3K-AKT pathway.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-18-0374</identifier><identifier>PMID: 30190422</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cell Survival - drug effects ; Drug Resistance, Neoplasm - drug effects ; Drug Synergism ; Glutathione - metabolism ; Humans ; Male ; Mice, SCID ; NF-E2-Related Factor 2 - metabolism ; Oxidation-Reduction ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Protein Kinase Inhibitors - pharmacology ; Protein Stability - drug effects ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - metabolism ; Proto-Oncogene Proteins c-pim-1 - metabolism ; Reactive Oxygen Species - metabolism ; Ubiquitination - drug effects ; Up-Regulation - drug effects</subject><ispartof>Molecular cancer therapeutics, 2018-12, Vol.17 (12), p.2710-2721</ispartof><rights>2018 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3264-eb45a4922c6dbea4d87e1c1381a733fb04cad2b9036f5aa70e5eb583ac0fb0093</citedby><cites>FETCH-LOGICAL-c3264-eb45a4922c6dbea4d87e1c1381a733fb04cad2b9036f5aa70e5eb583ac0fb0093</cites><orcidid>0000-0002-0123-2909 ; 0000-0002-1021-1827</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30190422$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Jin H</creatorcontrib><creatorcontrib>Singh, Neha</creatorcontrib><creatorcontrib>Luevano, Libia A</creatorcontrib><creatorcontrib>Padi, Sathish K R</creatorcontrib><creatorcontrib>Okumura, Koichi</creatorcontrib><creatorcontrib>Olive, Virginie</creatorcontrib><creatorcontrib>Black, Stephen M</creatorcontrib><creatorcontrib>Warfel, Noel A</creatorcontrib><creatorcontrib>Goodrich, David W</creatorcontrib><creatorcontrib>Kraft, Andrew S</creatorcontrib><title>Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Cancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element activity. PIM prevents cell death induced by PI3K-AKT-inhibitory drugs through a noncanonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity. Importantly, PIM also controls NAD(P)H production by increasing glucose flux through the pentose phosphate shunt decreasing ROS production, and thereby diminishing the cytotoxicity of PI3K-AKT inhibitors. Treatment with PIM kinase inhibitors reverses this resistance phenotype, making tumors increasingly susceptible to small-molecule therapeutics, which block the PI3K-AKT pathway.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Synergism</subject><subject>Glutathione - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Mice, SCID</subject><subject>NF-E2-Related Factor 2 - metabolism</subject><subject>Oxidation-Reduction</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoinositide-3 Kinase Inhibitors</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein Stability - drug effects</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Proto-Oncogene Proteins c-pim-1 - metabolism</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Ubiquitination - drug effects</subject><subject>Up-Regulation - drug effects</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkN1Kw0AQhRdRrFYfQdkXSN3fZHMjaPGntEUp9XrZ3UzMSpuUbCr07d1YLXo1w5w5Z4YPoStKRpRKdUMll0lGUz6aj5cJVQnhmThCZ3GuEiWpOP7u9zsDdB7CByFU5YyeogEnNCeCsTO0mIOrTO3DOuB7qHxd4AUEHzpTO8Bdg18nfIondeWt75oWL1sw3RrqLs6KrYMC2x3uKoh7czz1tQlwgU5Kswpw-VOH6O3xYTl-TmYvT5Px3SxxnKUiASukETljLi0sGFGoDKijXFGTcV5aIpwpmM0JT0tpTEZAgpWKG0eiSHI-RLf73M3WrqFw8anWrPSm9WvT7nRjvP6v1L7S782nTlmWS0VigNwHuLYJoYXy4KVE95B1D1D3AHWErKnSPeTou_57-OD6pcq_AD5LeUo</recordid><startdate>20181201</startdate><enddate>20181201</enddate><creator>Song, Jin H</creator><creator>Singh, Neha</creator><creator>Luevano, Libia A</creator><creator>Padi, Sathish K R</creator><creator>Okumura, Koichi</creator><creator>Olive, Virginie</creator><creator>Black, Stephen M</creator><creator>Warfel, Noel A</creator><creator>Goodrich, David W</creator><creator>Kraft, Andrew S</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>5PM</scope><orcidid>https://orcid.org/0000-0002-0123-2909</orcidid><orcidid>https://orcid.org/0000-0002-1021-1827</orcidid></search><sort><creationdate>20181201</creationdate><title>Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase</title><author>Song, Jin H ; Singh, Neha ; Luevano, Libia A ; Padi, Sathish K R ; Okumura, Koichi ; Olive, Virginie ; Black, Stephen M ; Warfel, Noel A ; Goodrich, David W ; Kraft, Andrew S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3264-eb45a4922c6dbea4d87e1c1381a733fb04cad2b9036f5aa70e5eb583ac0fb0093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Synergism</topic><topic>Glutathione - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Mice, SCID</topic><topic>NF-E2-Related Factor 2 - metabolism</topic><topic>Oxidation-Reduction</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoinositide-3 Kinase Inhibitors</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein Stability - drug effects</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Proto-Oncogene Proteins c-pim-1 - metabolism</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Ubiquitination - drug effects</topic><topic>Up-Regulation - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Song, Jin H</creatorcontrib><creatorcontrib>Singh, Neha</creatorcontrib><creatorcontrib>Luevano, Libia A</creatorcontrib><creatorcontrib>Padi, Sathish K R</creatorcontrib><creatorcontrib>Okumura, Koichi</creatorcontrib><creatorcontrib>Olive, Virginie</creatorcontrib><creatorcontrib>Black, Stephen M</creatorcontrib><creatorcontrib>Warfel, Noel A</creatorcontrib><creatorcontrib>Goodrich, David W</creatorcontrib><creatorcontrib>Kraft, Andrew S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Jin H</au><au>Singh, Neha</au><au>Luevano, Libia A</au><au>Padi, Sathish K R</au><au>Okumura, Koichi</au><au>Olive, Virginie</au><au>Black, Stephen M</au><au>Warfel, Noel A</au><au>Goodrich, David W</au><au>Kraft, Andrew S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2018-12-01</date><risdate>2018</risdate><volume>17</volume><issue>12</issue><spage>2710</spage><epage>2721</epage><pages>2710-2721</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Cancer resistance to PI3K inhibitor therapy can be in part mediated by increases in the PIM1 kinase. However, the exact mechanism by which PIM kinase promotes tumor cell resistance is unknown. Our study unveils the pivotal control of redox signaling by PIM kinases as a driver of this resistance mechanism. PIM1 kinase functions to decrease cellular ROS levels by enhancing nuclear factor erythroid 2-related factor 2 (NRF2)/antioxidant response element activity. PIM prevents cell death induced by PI3K-AKT-inhibitory drugs through a noncanonical mechanism of NRF2 ubiquitination and degradation and translational control of NRF2 protein levels through modulation of eIF4B and mTORC1 activity. Importantly, PIM also controls NAD(P)H production by increasing glucose flux through the pentose phosphate shunt decreasing ROS production, and thereby diminishing the cytotoxicity of PI3K-AKT inhibitors. 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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Cell Line, Tumor Cell Proliferation - drug effects Cell Survival - drug effects Drug Resistance, Neoplasm - drug effects Drug Synergism Glutathione - metabolism Humans Male Mice, SCID NF-E2-Related Factor 2 - metabolism Oxidation-Reduction Phosphatidylinositol 3-Kinases - metabolism Phosphoinositide-3 Kinase Inhibitors Protein Kinase Inhibitors - pharmacology Protein Stability - drug effects Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Proto-Oncogene Proteins c-pim-1 - metabolism Reactive Oxygen Species - metabolism Ubiquitination - drug effects Up-Regulation - drug effects |
| title | Mechanisms Behind Resistance to PI3K Inhibitor Treatment Induced by the PIM Kinase |
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