Inhibitors of Ras effector signaling are considered the most viable direction for successful development of effective anti-Ras therapies for the treatment of pancreatic ductal adenocarcinoma (PDAC), with most efforts focused on the Raf-MEK-ERK mitogen-activated protein kinase (MAPK) cascade. Eighteen Raf or MEK inhibitors are currently under Phase I-III clinical evaluation. However, signaling reprogramming mechanisms that restore ERK activation downstream of the inhibitor block, or that activate parallel activities to reduce ERK dependency, have severely limited their anti-tumor activities. SCH772984 is a recently developed novel, highly selective ATP-competitive and allosteric ERK1 and ERK2 inhibitor that is currently under Phase Ib clinical evaluation for RAS or BRAF mutant cancers. We propose studies to define signaling mechanisms that overcome ERK inhibition and drive ERK isoform differences, with the long-term goal to advance the clinical development of SCH772984 and other ERK inhibitors. First, our preliminary studies found SCH772984 more effective than MEK inhibition for blocking PDAC cell line anchorage-dependent and -independent growth. However, a subset of PDAC lines showed de novo (primary) resistance to SCH772984. We have also found that high-dose SCH772984 treatment of sensitive PDAC lines resulted in the outgrowth of subpopulations with acquired (secondary) resistance. We will apply druggable genome siRNA screens to identify genes that control de novo versus acquired PDAC resistance to SCH772984. We hypothesize that these studies will identify combination inhibitor approaches that synergistically enhance the anti-tumor activity of ERK inhibitors. Second, surprisingly, despite their high sequence and biochemical identity, we determined that ERK1 and ERK2 display distinct, non-overlapping essential functions in PDAC growth. A genome-wide phosphoproteomics approach will be applied to identify ERK isoform-specific substrates essential for PDAC growth. In addition to delineating novel signaling mechanisms driven by ERK activation, these studies may identify directions for isoform-selective anti-ERK therapeutic strategies. Our application of innovative strategies to study ERK-dependent PDAC growth are high risk;but with the critical importance of ERK in PDAC growth, our findings have high-gain potential for a breakthrough in PDAC therapy.

Public Health Relevance

It is widely agreed that a KRAS-targeted therapy will be an effective therapy for pancreatic cancer, the 4th cause of cancer deaths in the US, and projected to be the 2nd leading cause in 2015. Our studies will develop and advance ERK inhibitors as an anti-KRAS strategy for this deadly cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA179193-01A1
Application #
8643960
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Forry, Suzanne L
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$231,887
Indirect Cost
$45,432
Name
University of North Carolina Chapel Hill
Department
Pharmacology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Ryan, Meagan B; Finn, Alexander J; Pedone, Katherine H et al. (2016) ERK/MAPK Signaling Drives Overexpression of the Rac-GEF, PREX1, in BRAF- and NRAS-Mutant Melanoma. Mol Cancer Res 14:1009-1018
Lawson, Campbell D; Fan, Cheng; Mitin, Natalia et al. (2016) Rho GTPase Transcriptome Analysis Reveals Oncogenic Roles for Rho GTPase-Activating Proteins in Basal-like Breast Cancers. Cancer Res 76:3826-37
Hayes, Tikvah K; Neel, Nicole F; Hu, Chaoxin et al. (2016) Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression. Cancer Cell 29:75-89
Hobbs, G Aaron; Der, Channing J; Rossman, Kent L (2016) RAS isoforms and mutations in cancer at a glance. J Cell Sci 129:1287-92
Zhou, Bingying; Der, Channing J; Cox, Adrienne D (2016) The role of wild type RAS isoforms in cancer. Semin Cell Dev Biol 58:60-9
Zhou, Bingying; Ritt, Daniel A; Morrison, Deborah K et al. (2016) Protein Kinase CK2α Maintains Extracellular Signal-regulated Kinase (ERK) Activity in a CK2α Kinase-independent Manner to Promote Resistance to Inhibitors of RAF and MEK but Not ERK in BRAF Mutant Melanoma. J Biol Chem 291:17804-15
Ryan, Meagan B; Der, Channing J; Wang-Gillam, Andrea et al. (2015) Targeting RAS-mutant cancers: is ERK the key? Trends Cancer 1:183-198
Cox, Adrienne D; Der, Channing J; Philips, Mark R (2015) Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery? Clin Cancer Res 21:1819-27
Baker, Nicole M; Yee Chow, Hoi; Chernoff, Jonathan et al. (2014) Molecular pathways: targeting RAC-p21-activated serine-threonine kinase signaling in RAS-driven cancers. Clin Cancer Res 20:4740-6
Cox, Adrienne D; Fesik, Stephen W; Kimmelman, Alec C et al. (2014) Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov 13:828-51

Showing the most recent 10 out of 12 publications