Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

Tikvah K Hayes; Nicole F Neel; Chaoxin Hu; Prson Gautam; Melissa Chenard; Brian Long; Meraj Aziz; Michelle Kassner; Kirsten L Bryant; Mariaelena Pierobon; Raoud Marayati; Swapnil Kher; Samuel D George; Mai Xu; Andrea Wang-Gillam; Ahmed A Samatar; Anirban Maitra; Krister Wennerberg; Emanuel F Petricoin; Hongwei H Yin; Barry Nelkin; Adrienne D Cox; Jen Jen Yeh; Channing J Der

doi:10.1016/j.ccell.2015.11.011

Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

Tikvah K Hayes, Nicole F Neel, Chaoxin Hu, Prson Gautam, Melissa Chenard, Brian Long, Meraj Aziz, Michelle Kassner, Kirsten L Bryant, Mariaelena Pierobon, Raoud Marayati, Swapnil Kher, Samuel D George, Mai Xu, Andrea Wang-Gillam, Ahmed A Samatar, Anirban Maitra, Krister Wennerberg, Emanuel F Petricoin, Hongwei H YinBarry Nelkin, Adrienne D Cox, Jen Jen Yeh, Channing J Der

120 Citationer (Scopus)

Abstract

Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK. Hayes et al. report an ERK inhibition-mediated growth suppression mechanism involving MYC degradation that is associated with the induction of a senescence-like phenotype in KRAS-mutant pancreatic cancer cells. Inhibitor combinations that enhance the effect of ERK inhibitor are also identified.

Originalsprog	Engelsk
Tidsskrift	Cancer Cell
Vol/bind	29
Udgave nummer	1
Sider (fra-til)	75-89
Antal sider	15
ISSN	1535-6108
DOI	https://doi.org/10.1016/j.ccell.2015.11.011
Status	Udgivet - 11 jan. 2016
Udgivet eksternt	Ja

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10.1016/j.ccell.2015.11.011

http://www.cell.com/article/S153561081500433X/pdf

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Hayes, T. K., Neel, N. F., Hu, C., Gautam, P., Chenard, M., Long, B., Aziz, M., Kassner, M., Bryant, K. L., Pierobon, M., Marayati, R., Kher, S., George, S. D., Xu, M., Wang-Gillam, A., Samatar, A. A., Maitra, A., Wennerberg, K., Petricoin, E. F., ... Der, C. J. (2016). Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. Cancer Cell, 29(1), 75-89. https://doi.org/10.1016/j.ccell.2015.11.011

Hayes, TK, Neel, NF, Hu, C, Gautam, P, Chenard, M, Long, B, Aziz, M, Kassner, M, Bryant, KL, Pierobon, M, Marayati, R, Kher, S, George, SD, Xu, M, Wang-Gillam, A, Samatar, AA, Maitra, A, Wennerberg, K, Petricoin, EF, Yin, HH, Nelkin, B, Cox, AD, Yeh, JJ & Der, CJ 2016, 'Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression', Cancer Cell, bind 29, nr. 1, s. 75-89. https://doi.org/10.1016/j.ccell.2015.11.011

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title = "Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression",

abstract = "Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK. Hayes et al. report an ERK inhibition-mediated growth suppression mechanism involving MYC degradation that is associated with the induction of a senescence-like phenotype in KRAS-mutant pancreatic cancer cells. Inhibitor combinations that enhance the effect of ERK inhibitor are also identified.",

keywords = "Animals, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases/genetics, MAP Kinase Signaling System/genetics, Mice, Mitogen-Activated Protein Kinase Kinases/genetics, Pancreatic Neoplasms/genetics, Phosphatidylinositol 3-Kinases/metabolism, Protein Kinase Inhibitors/pharmacology, Proto-Oncogene Proteins c-akt/metabolism, Proto-Oncogene Proteins c-myc/genetics, Proto-Oncogene Proteins p21(ras)/genetics, Time",

author = "Hayes, {Tikvah K} and Neel, {Nicole F} and Chaoxin Hu and Prson Gautam and Melissa Chenard and Brian Long and Meraj Aziz and Michelle Kassner and Bryant, {Kirsten L} and Mariaelena Pierobon and Raoud Marayati and Swapnil Kher and George, {Samuel D} and Mai Xu and Andrea Wang-Gillam and Samatar, {Ahmed A} and Anirban Maitra and Krister Wennerberg and Petricoin, {Emanuel F} and Yin, {Hongwei H} and Barry Nelkin and Cox, {Adrienne D} and Yeh, {Jen Jen} and Der, {Channing J}",

year = "2016",

month = jan,

day = "11",

doi = "10.1016/j.ccell.2015.11.011",

language = "English",

volume = "29",

pages = "75--89",

journal = "Cancer Cell",

issn = "1535-6108",

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T1 - Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

AU - Hayes, Tikvah K

AU - Neel, Nicole F

AU - Hu, Chaoxin

AU - Gautam, Prson

AU - Chenard, Melissa

AU - Long, Brian

AU - Aziz, Meraj

AU - Kassner, Michelle

AU - Bryant, Kirsten L

AU - Pierobon, Mariaelena

AU - Marayati, Raoud

AU - Kher, Swapnil

AU - George, Samuel D

AU - Xu, Mai

AU - Wang-Gillam, Andrea

AU - Samatar, Ahmed A

AU - Maitra, Anirban

AU - Wennerberg, Krister

AU - Petricoin, Emanuel F

AU - Yin, Hongwei H

AU - Nelkin, Barry

AU - Cox, Adrienne D

AU - Yeh, Jen Jen

AU - Der, Channing J

PY - 2016/1/11

Y1 - 2016/1/11

N2 - Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK. Hayes et al. report an ERK inhibition-mediated growth suppression mechanism involving MYC degradation that is associated with the induction of a senescence-like phenotype in KRAS-mutant pancreatic cancer cells. Inhibitor combinations that enhance the effect of ERK inhibitor are also identified.

AB - Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK. Hayes et al. report an ERK inhibition-mediated growth suppression mechanism involving MYC degradation that is associated with the induction of a senescence-like phenotype in KRAS-mutant pancreatic cancer cells. Inhibitor combinations that enhance the effect of ERK inhibitor are also identified.

KW - Animals

KW - Cell Line, Tumor

KW - Extracellular Signal-Regulated MAP Kinases/genetics

KW - MAP Kinase Signaling System/genetics

KW - Mice

KW - Mitogen-Activated Protein Kinase Kinases/genetics

KW - Pancreatic Neoplasms/genetics

KW - Phosphatidylinositol 3-Kinases/metabolism

KW - Protein Kinase Inhibitors/pharmacology

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Proto-Oncogene Proteins c-myc/genetics

KW - Proto-Oncogene Proteins p21(ras)/genetics

KW - Time

U2 - 10.1016/j.ccell.2015.11.011

DO - 10.1016/j.ccell.2015.11.011

M3 - Journal article

C2 - 26725216

SN - 1535-6108

VL - 29

SP - 75

EP - 89

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

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