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 Citations (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.

Original language	English
Journal	Cancer Cell
Volume	29
Issue number	1
Pages (from-to)	75-89
Number of pages	15
ISSN	1535-6108
DOIs	https://doi.org/10.1016/j.ccell.2015.11.011
Publication status	Published - 11 Jan 2016
Externally published	Yes

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2015.11.011

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

Cite this

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, vol. 29, no. 1, pp. 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}",

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

language = "English",

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journal = "Cancer Cell",

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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

Abstract

Keywords

UN SDGs

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