Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

Jeffrey A. Klomp; Jennifer E. Klomp; Clint A. Stalnecker; Kirsten L. Bryant; A. Cole Edwards; Kristina Drizyte-Miller; Priya S. Hibshman; J. Nathaniel Diehl; Ye S. Lee; Alexis J. Morales; Khalilah E. Taylor; Sen Peng; Nhan L. Tran; Laura E. Herring; Alex W. Prevatte; Natalie K. Barker; Laura D. Hover; Jill Hallin; Saikat Chowdhury; Oluwadara Coker; Hey Min Lee; Craig M. Goodwin; Prson Gautam; Peter Olson; James G. Christensen; John P. Shen; Scott Kopetz; Lee M. Graves; Kian Huat Lim; Andrea Wang-Gillam; Krister Wennerberg; Adrienne D. Cox; Channing J. Der

doi:10.1126/science.adk0775

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

Jeffrey A. Klomp, Jennifer E. Klomp, Clint A. Stalnecker, Kirsten L. Bryant, A. Cole Edwards, Kristina Drizyte-Miller, Priya S. Hibshman, J. Nathaniel Diehl, Ye S. Lee, Alexis J. Morales, Khalilah E. Taylor, Sen Peng, Nhan L. Tran, Laura E. Herring, Alex W. Prevatte, Natalie K. Barker, Laura D. Hover, Jill Hallin, Saikat Chowdhury, Oluwadara CokerHey Min Lee, Craig M. Goodwin, Prson Gautam, Peter Olson, James G. Christensen, John P. Shen, Scott Kopetz, Lee M. Graves, Kian Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D. Cox, Channing J. Der

Research output: Contribution to journal › Article › peer-review

Abstract

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

Original language	English
Pages (from-to)	eadk0775
Journal	Science (New York, N.Y.)
Volume	384
Issue number	6700
DOIs	https://doi.org/10.1126/science.adk0775
State	Published - Jun 7 2024

Access to Document

10.1126/science.adk0775

Cite this

Klomp, J. A., Klomp, J. E., Stalnecker, C. A., Bryant, K. L., Edwards, A. C., Drizyte-Miller, K., Hibshman, P. S., Diehl, J. N., Lee, Y. S., Morales, A. J., Taylor, K. E., Peng, S., Tran, N. L., Herring, L. E., Prevatte, A. W., Barker, N. K., Hover, L. D., Hallin, J., Chowdhury, S., ... Der, C. J. (2024). Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers. Science (New York, N.Y.), 384(6700), eadk0775. https://doi.org/10.1126/science.adk0775

@article{965de2b1cbd04ecead842e347b499a27,

title = "Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers",

abstract = "How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.",

author = "Klomp, {Jeffrey A.} and Klomp, {Jennifer E.} and Stalnecker, {Clint A.} and Bryant, {Kirsten L.} and Edwards, {A. Cole} and Kristina Drizyte-Miller and Hibshman, {Priya S.} and Diehl, {J. Nathaniel} and Lee, {Ye S.} and Morales, {Alexis J.} and Taylor, {Khalilah E.} and Sen Peng and Tran, {Nhan L.} and Herring, {Laura E.} and Prevatte, {Alex W.} and Barker, {Natalie K.} and Hover, {Laura D.} and Jill Hallin and Saikat Chowdhury and Oluwadara Coker and Lee, {Hey Min} and Goodwin, {Craig M.} and Prson Gautam and Peter Olson and Christensen, {James G.} and Shen, {John P.} and Scott Kopetz and Graves, {Lee M.} and Lim, {Kian Huat} and Andrea Wang-Gillam and Krister Wennerberg and Cox, {Adrienne D.} and Der, {Channing J.}",

year = "2024",

month = jun,

day = "7",

doi = "10.1126/science.adk0775",

language = "English",

volume = "384",

pages = "eadk0775",

journal = "Science (New York, N.Y.)",

issn = "0036-8075",

number = "6700",

}

Klomp, JA, Klomp, JE, Stalnecker, CA, Bryant, KL, Edwards, AC, Drizyte-Miller, K, Hibshman, PS, Diehl, JN, Lee, YS, Morales, AJ, Taylor, KE, Peng, S, Tran, NL, Herring, LE, Prevatte, AW, Barker, NK, Hover, LD, Hallin, J, Chowdhury, S, Coker, O, Lee, HM, Goodwin, CM, Gautam, P, Olson, P, Christensen, JG, Shen, JP, Kopetz, S, Graves, LM, Lim, KH , Wang-Gillam, A, Wennerberg, K, Cox, AD & Der, CJ 2024, 'Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers', Science (New York, N.Y.), vol. 384, no. 6700, pp. eadk0775. https://doi.org/10.1126/science.adk0775

TY - JOUR

T1 - Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

AU - Klomp, Jeffrey A.

AU - Klomp, Jennifer E.

AU - Stalnecker, Clint A.

AU - Bryant, Kirsten L.

AU - Edwards, A. Cole

AU - Drizyte-Miller, Kristina

AU - Hibshman, Priya S.

AU - Diehl, J. Nathaniel

AU - Lee, Ye S.

AU - Morales, Alexis J.

AU - Taylor, Khalilah E.

AU - Peng, Sen

AU - Tran, Nhan L.

AU - Herring, Laura E.

AU - Prevatte, Alex W.

AU - Barker, Natalie K.

AU - Hover, Laura D.

AU - Hallin, Jill

AU - Chowdhury, Saikat

AU - Coker, Oluwadara

AU - Lee, Hey Min

AU - Goodwin, Craig M.

AU - Gautam, Prson

AU - Olson, Peter

AU - Christensen, James G.

AU - Shen, John P.

AU - Kopetz, Scott

AU - Graves, Lee M.

AU - Lim, Kian Huat

AU - Wang-Gillam, Andrea

AU - Wennerberg, Krister

AU - Cox, Adrienne D.

AU - Der, Channing J.

PY - 2024/6/7

Y1 - 2024/6/7

N2 - How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

AB - How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal-regulated kinase (ERK)-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

UR - http://www.scopus.com/inward/record.url?scp=85195438625&partnerID=8YFLogxK

U2 - 10.1126/science.adk0775

DO - 10.1126/science.adk0775

M3 - Article

C2 - 38843331

AN - SCOPUS:85195438625

SN - 0036-8075

VL - 384

SP - eadk0775

JO - Science (New York, N.Y.)

JF - Science (New York, N.Y.)

IS - 6700

ER -

Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers

Abstract

Access to Document

Other files and links

Fingerprint

Cite this