Klomp, Jennifer E
Mayo Clinic
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Citations 2
Defining the MYC-regulated transcriptome and kinome that support KRAS- and ERK-dependent growth of pancreatic cancer
Hibshman, Priya S. , Stalnecker, Clint A. , Drizyte‐Miller, Kristina , Klomp, Jennifer E. , Edwards, A. Cole , Pita, Lily M. , Hodge, Richard G. , Diehl, J. Nathaniel , Mouery, Ryan D. , Mouery, Brandon L. , Snare, Kayla R., Waters, Andrew M. , Peng, Sen, Barker, Natalie K. , Pierobon, Mariaelena , Rashid, Naim U. , Tran, Nhan L. , Herring, Laura E. , Graves, Lee M. , Petricoin, Emanuel F. , Bryant, Kirsten L. , Cox, Adrienne D. , Klomp, Jeffrey A , Drizyte-Miller, Kristina , Klomp, Jennifer E , Edwards, A Cole , Hodge, Richard G , Diehl, J Nathaniel , Mouery, Brandon L , Snare, Kayla R , Waters, Andrew M , Barker, Natalie K , Herring, Laura E , Graves, Lee M , Petricoin, Emanuel F , Bryant, Kirsten L , Cox, Adrienne D , Der, Channing J , Stalnecker, Clint A , Tran, Nhan L
Science Signaling | September 30, 2025 | Volume: 18 | Issue: 906 | Pages: No page available
Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS -mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.
Defining the KRAS- and ERK-dependent transcriptome in KRAS-mutant cancers
Klomp, Jennifer E. , Stalnecker, Clint A. , Bryant, Kirsten L. , Edwards, A. Cole , Drizyte‐Miller, Kristina , Hibshman, Priya S. , Diehl, J. Nathaniel , Lee, Ye S. , Morales, Alexis Jean , Taylor, Khalilah E. , Peng, Sen, Tran, Nhan L. , Prevatte, Alex W., Hover, Laura D. , Hallin, Jill , Chowdhury, Saikat , Coker, Oluwadara , Olson, Peter , Christensen, James G. , Graves, Lee M. , Wennerberg, Krister , Klomp, Jeffrey A , Klomp, Jennifer E , Stalnecker, Clint A , Bryant, Kirsten L , Drizyte-Miller, Kristina , Diehl, J Nathaniel , Lee, Ye S , Morales, Alexis J , Taylor, Khalilah E , Herring, Laura E , Barker, Natalie K , Hallin, Jill , Chowdhury, Saikat , Coker, Oluwadara , Lee, Hey Min , Goodwin, Craig M , Gautam, Prson , Olson, Peter , Christensen, James G , Shen, John P , Kopetz, Scott , Graves, Lee M , Lim, Kian-Huat , Wang-Gillam, Andrea , Wennerberg, Krister , Cox, Adrienne D , Der, Channing J , Tran, Nhan L , Herring, Laura E. , Barker, Natalie K. , Gautam, Prson , Kopetz, Scott , Wang‐Gillam, Andrea , Cox, Adrienne D.
Science | June 6, 2024 | Volume: 384 | Issue: 6700 | Pages: No page available
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.