Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition

Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexp...
Ausführliche Beschreibung

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Autor*in:	Claas, Allison M. [verfasserIn] Atta, Lyla Gordonov, Simon Meyer, Aaron S. Lauffenburger, Douglas A.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2018

Schlagwörter:	Triple negative breast cancer EGFR Her2 Met Axl Mek inhibition Erk inhibition BET inhibition

Anmerkung:	© The Author(s) 2018

Übergeordnetes Werk:	Enthalten in: Cellular and molecular bioengineering - New Yok, NY [u.a.] : Springer, 2008, 11(2018), 6 vom: 26. Juli, Seite 451-469
Übergeordnetes Werk:	volume:11 ; year:2018 ; number:6 ; day:26 ; month:07 ; pages:451-469

Links:	Volltext

DOI / URN:	10.1007/s12195-018-0542-y

Katalog-ID:	SPR025187406

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100	1		\|a Claas, Allison M. \|e verfasserin \|4 aut
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520			\|a Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development.
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650		4	\|a Mek inhibition \|7 (dpeaa)DE-He213
650		4	\|a Erk inhibition \|7 (dpeaa)DE-He213
650		4	\|a BET inhibition \|7 (dpeaa)DE-He213
700	1		\|a Atta, Lyla \|4 aut
700	1		\|a Gordonov, Simon \|4 aut
700	1		\|a Meyer, Aaron S. \|4 aut
700	1		\|a Lauffenburger, Douglas A. \|0 (orcid)0000-0002-0050-989X \|4 aut
773	0	8	\|i Enthalten in \|t Cellular and molecular bioengineering \|d New Yok, NY [u.a.] : Springer, 2008 \|g 11(2018), 6 vom: 26. Juli, Seite 451-469 \|w (DE-627)560179030 \|w (DE-600)2416037-4 \|x 1865-5033 \|7 nnns
773	1	8	\|g volume:11 \|g year:2018 \|g number:6 \|g day:26 \|g month:07 \|g pages:451-469
856	4	0	\|u https://dx.doi.org/10.1007/s12195-018-0542-y \|z kostenfrei \|3 Volltext
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912			\|a GBV_ILN_138
912			\|a GBV_ILN_150
912			\|a GBV_ILN_151
912			\|a GBV_ILN_161
912			\|a GBV_ILN_170
912			\|a GBV_ILN_171
912			\|a GBV_ILN_187
912			\|a GBV_ILN_213
912			\|a GBV_ILN_224
912			\|a GBV_ILN_230
912			\|a GBV_ILN_250
912			\|a GBV_ILN_281
912			\|a GBV_ILN_285
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912			\|a GBV_ILN_2061
912			\|a GBV_ILN_2064
912			\|a GBV_ILN_2065
912			\|a GBV_ILN_2068
912			\|a GBV_ILN_2070
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912			\|a GBV_ILN_4046
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allfields	10.1007/s12195-018-0542-y doi (DE-627)SPR025187406 (SPR)s12195-018-0542-y-e DE-627 ger DE-627 rakwb eng Claas, Allison M. verfasserin aut Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. Triple negative breast cancer (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Her2 (dpeaa)DE-He213 Met (dpeaa)DE-He213 Axl (dpeaa)DE-He213 Mek inhibition (dpeaa)DE-He213 Erk inhibition (dpeaa)DE-He213 BET inhibition (dpeaa)DE-He213 Atta, Lyla aut Gordonov, Simon aut Meyer, Aaron S. aut Lauffenburger, Douglas A. (orcid)0000-0002-0050-989X aut Enthalten in Cellular and molecular bioengineering New Yok, NY [u.a.] : Springer, 2008 11(2018), 6 vom: 26. Juli, Seite 451-469 (DE-627)560179030 (DE-600)2416037-4 1865-5033 nnns volume:11 year:2018 number:6 day:26 month:07 pages:451-469 https://dx.doi.org/10.1007/s12195-018-0542-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 11 2018 6 26 07 451-469
spelling	10.1007/s12195-018-0542-y doi (DE-627)SPR025187406 (SPR)s12195-018-0542-y-e DE-627 ger DE-627 rakwb eng Claas, Allison M. verfasserin aut Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. Triple negative breast cancer (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Her2 (dpeaa)DE-He213 Met (dpeaa)DE-He213 Axl (dpeaa)DE-He213 Mek inhibition (dpeaa)DE-He213 Erk inhibition (dpeaa)DE-He213 BET inhibition (dpeaa)DE-He213 Atta, Lyla aut Gordonov, Simon aut Meyer, Aaron S. aut Lauffenburger, Douglas A. (orcid)0000-0002-0050-989X aut Enthalten in Cellular and molecular bioengineering New Yok, NY [u.a.] : Springer, 2008 11(2018), 6 vom: 26. Juli, Seite 451-469 (DE-627)560179030 (DE-600)2416037-4 1865-5033 nnns volume:11 year:2018 number:6 day:26 month:07 pages:451-469 https://dx.doi.org/10.1007/s12195-018-0542-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 11 2018 6 26 07 451-469
allfields_unstemmed	10.1007/s12195-018-0542-y doi (DE-627)SPR025187406 (SPR)s12195-018-0542-y-e DE-627 ger DE-627 rakwb eng Claas, Allison M. verfasserin aut Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. Triple negative breast cancer (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Her2 (dpeaa)DE-He213 Met (dpeaa)DE-He213 Axl (dpeaa)DE-He213 Mek inhibition (dpeaa)DE-He213 Erk inhibition (dpeaa)DE-He213 BET inhibition (dpeaa)DE-He213 Atta, Lyla aut Gordonov, Simon aut Meyer, Aaron S. aut Lauffenburger, Douglas A. (orcid)0000-0002-0050-989X aut Enthalten in Cellular and molecular bioengineering New Yok, NY [u.a.] : Springer, 2008 11(2018), 6 vom: 26. Juli, Seite 451-469 (DE-627)560179030 (DE-600)2416037-4 1865-5033 nnns volume:11 year:2018 number:6 day:26 month:07 pages:451-469 https://dx.doi.org/10.1007/s12195-018-0542-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 11 2018 6 26 07 451-469
allfieldsGer	10.1007/s12195-018-0542-y doi (DE-627)SPR025187406 (SPR)s12195-018-0542-y-e DE-627 ger DE-627 rakwb eng Claas, Allison M. verfasserin aut Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. Triple negative breast cancer (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Her2 (dpeaa)DE-He213 Met (dpeaa)DE-He213 Axl (dpeaa)DE-He213 Mek inhibition (dpeaa)DE-He213 Erk inhibition (dpeaa)DE-He213 BET inhibition (dpeaa)DE-He213 Atta, Lyla aut Gordonov, Simon aut Meyer, Aaron S. aut Lauffenburger, Douglas A. (orcid)0000-0002-0050-989X aut Enthalten in Cellular and molecular bioengineering New Yok, NY [u.a.] : Springer, 2008 11(2018), 6 vom: 26. Juli, Seite 451-469 (DE-627)560179030 (DE-600)2416037-4 1865-5033 nnns volume:11 year:2018 number:6 day:26 month:07 pages:451-469 https://dx.doi.org/10.1007/s12195-018-0542-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 11 2018 6 26 07 451-469
allfieldsSound	10.1007/s12195-018-0542-y doi (DE-627)SPR025187406 (SPR)s12195-018-0542-y-e DE-627 ger DE-627 rakwb eng Claas, Allison M. verfasserin aut Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition 2018 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2018 Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. Triple negative breast cancer (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Her2 (dpeaa)DE-He213 Met (dpeaa)DE-He213 Axl (dpeaa)DE-He213 Mek inhibition (dpeaa)DE-He213 Erk inhibition (dpeaa)DE-He213 BET inhibition (dpeaa)DE-He213 Atta, Lyla aut Gordonov, Simon aut Meyer, Aaron S. aut Lauffenburger, Douglas A. (orcid)0000-0002-0050-989X aut Enthalten in Cellular and molecular bioengineering New Yok, NY [u.a.] : Springer, 2008 11(2018), 6 vom: 26. Juli, Seite 451-469 (DE-627)560179030 (DE-600)2416037-4 1865-5033 nnns volume:11 year:2018 number:6 day:26 month:07 pages:451-469 https://dx.doi.org/10.1007/s12195-018-0542-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_250 GBV_ILN_281 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2031 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2039 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2070 GBV_ILN_2086 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2107 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2116 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2446 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 AR 11 2018 6 26 07 451-469
language	English
source	Enthalten in Cellular and molecular bioengineering 11(2018), 6 vom: 26. Juli, Seite 451-469 volume:11 year:2018 number:6 day:26 month:07 pages:451-469
sourceStr	Enthalten in Cellular and molecular bioengineering 11(2018), 6 vom: 26. Juli, Seite 451-469 volume:11 year:2018 number:6 day:26 month:07 pages:451-469
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Triple negative breast cancer EGFR Her2 Met Axl Mek inhibition Erk inhibition BET inhibition
isfreeaccess_bool	true
container_title	Cellular and molecular bioengineering
authorswithroles_txt_mv	Claas, Allison M. @@aut@@ Atta, Lyla @@aut@@ Gordonov, Simon @@aut@@ Meyer, Aaron S. @@aut@@ Lauffenburger, Douglas A. @@aut@@
publishDateDaySort_date	2018-07-26T00:00:00Z
hierarchy_top_id	560179030
id	SPR025187406
language_de	englisch
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Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. 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author	Claas, Allison M.
spellingShingle	Claas, Allison M. misc Triple negative breast cancer misc EGFR misc Her2 misc Met misc Axl misc Mek inhibition misc Erk inhibition misc BET inhibition Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition
authorStr	Claas, Allison M.
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topic_title	Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition Triple negative breast cancer (dpeaa)DE-He213 EGFR (dpeaa)DE-He213 Her2 (dpeaa)DE-He213 Met (dpeaa)DE-He213 Axl (dpeaa)DE-He213 Mek inhibition (dpeaa)DE-He213 Erk inhibition (dpeaa)DE-He213 BET inhibition (dpeaa)DE-He213
topic	misc Triple negative breast cancer misc EGFR misc Her2 misc Met misc Axl misc Mek inhibition misc Erk inhibition misc BET inhibition
topic_unstemmed	misc Triple negative breast cancer misc EGFR misc Her2 misc Met misc Axl misc Mek inhibition misc Erk inhibition misc BET inhibition
topic_browse	misc Triple negative breast cancer misc EGFR misc Her2 misc Met misc Axl misc Mek inhibition misc Erk inhibition misc BET inhibition
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title	Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition
ctrlnum	(DE-627)SPR025187406 (SPR)s12195-018-0542-y-e
title_full	Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition
author_sort	Claas, Allison M.
journal	Cellular and molecular bioengineering
journalStr	Cellular and molecular bioengineering
lang_code	eng
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container_start_page	451
author_browse	Claas, Allison M. Atta, Lyla Gordonov, Simon Meyer, Aaron S. Lauffenburger, Douglas A.
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format_se	Elektronische Aufsätze
author-letter	Claas, Allison M.
doi_str_mv	10.1007/s12195-018-0542-y
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title_sort	systems modeling identifies divergent receptor tyrosine kinase reprogramming to mapk pathway inhibition
title_auth	Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition
abstract	Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. © The Author(s) 2018
abstractGer	Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. © The Author(s) 2018
abstract_unstemmed	Introduction Targeted cancer therapeutics have demonstrated more limited clinical efficacy than anticipated, due to both intrinsic and acquired drug resistance. Underlying mechanisms have been largely attributed to genetic changes, but a substantial proportion of resistance observations remain unexplained by genomic properties. Emerging evidence shows that receptor tyrosine kinase (RTK) reprogramming is a major alternative process causing targeted drug resistance, separate from genetic alterations. Hence, the contributions of mechanisms leading to this process need to be more rigorously assessed. Methods To parse contributions of multiple mechanisms to RTK reprogramming, we have developed a quantitative multi-receptor and multi-mechanistic experimental framework and kinetic model. Results We find that RTK reprogramming mechanisms are disparate among RTKs and nodes of intervention in the MAPK pathway. Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. Conclusions Our findings suggest that RTK reprogramming occurs through multiple mechanisms in a MAPK pathway target-specific manner, highlighting the need for comprehensive resistance mechanism profiling strategies during pharmacological development. © The Author(s) 2018
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container_issue	6
title_short	Systems Modeling Identifies Divergent Receptor Tyrosine Kinase Reprogramming to MAPK Pathway Inhibition
url	https://dx.doi.org/10.1007/s12195-018-0542-y
remote_bool	true
author2	Atta, Lyla Gordonov, Simon Meyer, Aaron S. Lauffenburger, Douglas A.
author2Str	Atta, Lyla Gordonov, Simon Meyer, Aaron S. Lauffenburger, Douglas A.
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doi_str	10.1007/s12195-018-0542-y
up_date	2024-07-03T14:25:34.833Z
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Mek inhibition induces increased Axl and Her2 levels in triple negative breast cancer (TNBC) cells while Met and EGFR levels remain unchanged, with Axl and Her2 sharing re-wiring through increased synthesis and differing secondary contributing mechanisms. While three Mek inhibitors exhibited mechanistic similarity, three Erk inhibitors elicited effects different from the Mek inhibitors and from each other, with MAPK pathway target-specific effects correlating with Erk subcellular localization. Furthermore, we find that Mek inhibitor-induced RTK reprogramming occurs through both BET bromodomain dependent and independent mechanisms, motivating combination treatment with BET and Axl inhibition to overcome RTK reprogramming. 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