Exploiting the distinct genomics and signaling of colorectal cancers to effectively target ERK

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

↗ Live URL (may be dead)

Document text

Principal Investigator: Rona  Yaeger
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $237,941
Funding agency: National Cancer Institute

Genomic and biochemical studies indicate the central role of ERK signaling as the key driver of
colorectal cancer (CRC) proliferation. Yet selective RAF/MEK/ERK pathway inhibitors have
been ineffective in the treatment of CRC thus far. We hypothesize that profound ERK inhibition
is required to suppress the growth of ERK activated tumors and that high basal receptor-driven
RAS activation in CRC causes rapid adaptive and acquired resistance to ERK inhibition that is
not overcome with current inhibitors due to their narrow therapeutic index. Additionally,
augmenting this high basal receptor-driven RAS activation could provide sufficient ERK
activation to stimulate tumor growth, providing a selective pressure for genomic alterations that
amplify upstream signaling in CRC. In this proposal, we will define the spectrum of genomic
alterations in CRC that amplify ERK signaling and could be targeted with ERK inhibition and will
functionally and biochemically characterize novel alterations in the RAF and MEK proteins. We
will devise strategies that profoundly inhibit ERK by co-targeting ERK activation and receptor re-
activation and by using novel combinations and dosing schedules that expand the therapeutic
index of ERK inhibition. We have shown that high receptor tyrosine kinase (RTK) signaling in
CRC has consequences for response to targeted therapies as (1) response rates to RAF plus
RTK (i.e., EGFR) inhibitors is better than for RAF inhibitors alone in patients with BRAF V600E
CRC, (2) wild-type RAS amplification, a recurrent mechanism of resistance to RAF inhibitor
combinations in CRC never detected in the large number of analyzed RAF inhibitor-resistant
melanomas, increases activated RAS in an RTK-dependent manner, and (3) low activity BRAF
mutants in CRC can act as oncogenes by increasing signal transduction from activated RAS
and amplifying EGFR signaling. This proposal will now apply an understanding of these specific
lineage properties to define the molecular profiles that depend on ERK signaling and devise
effective strategies to inhibit ERK signaling in CRC in the clinic. We believe these studies will
guide the development of new treatments for CRC and improve the outcomes of patients with
these tumors.

Terms: <Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Advanced Cancer><Advanced Malignant Neoplasm><Attenuated><B-raf-1><BRAF><BRAF gene><Binding><Biochemical><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer-Promoting Gene><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Clinic><Clinical><Cloning><Colon or Rectum><Colorectal><Colorectal Cancer><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Development><Dose><EGF Receptor><EGFR><ERBB Protein><Environment><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><Feedback><Generalized Growth><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Genomics><Goals><Growth><HER1><In Vitro><Incidence><Intracellular Communication and Signaling><Keratinocyte cancer><Kinases><Kinetics><Ligands><Lung Carcinoma><MEKs><Malignant Melanoma><Mediating><Melanoma><Mill Hill-2 Viral Oncogene Homolog><Minority><Modeling><Molecular Fingerprinting><Molecular Interaction><Molecular Profiling><Mutation><NF-1><NF-1 Protein><NF-1 encoded protein><NF1><NF1 GRP><NF1 Protein><NF1 gene><NF1 mutation><NF1-GAP-Related Protein><Neurofibromatosis 1 Genes><Neurofibromatosis Type 1 Gene Product><Neurofibromatosis Type 1 Protein><Neurofibromin><Neurofibromin 1><Non-Receptor Type 11 Protein Tyrosine Phosphatase><Normal Tissue><Normal tissue morphology><Oncogenes><PDX model><PTK Receptors><PTP-2 enzyme><PTP2C><PTPN11><PTPN11 gene><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pattern><Phosphotransferase Gene><Phosphotransferases><Proliferating><Property><Protein Tyrosine Phosphatase 2C><Protein-Tyrosine Phosphatase 2C><Proteins><RAF-1><RAF1><RAF1 gene><RAFB1><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Recurrence><Recurrent><Resistance><Role><SHP2><SHP2 Phosphatase><SHPTP2><Sampling><Schedule><Sequence Alteration><Series><Shp-2 tyrosine phosphatase><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><TGF-alpha Receptor><Testing><Therapeutic Index><Tissue Growth><Toxic effect><Toxicities><Transforming Genes><Transforming Growth Factor alpha Receptor><Transmembrane Receptor Protein Tyrosine Kinase><Transphosphorylases><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Tyrosine Phosphatase SHP2><Urogastrone Receptor><adapter protein><attenuate><attenuates><biological signal transduction><c-erbB-1><c-erbB-1 Protein><clinical development><colon cancer patients><colorectal cancer patients><colorectal cancer therapy><colorectal cancer treatment><colorectum><determine efficacy><developmental><dimer><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><epigenetically><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><evaluate efficacy><examine efficacy><genome mutation><genomic alteration><improved outcome><in vivo><in vivo Model><inhibitor><molecular profile><molecular signature><mutant><neurofibromatosis type 1 gene><neurofibromatosis type 1 protein/gene><nf 1 Genes><novel><ontogeny><pathway><patient derived xenograft model><patient oriented outcomes><pre-clinical evaluation><preclinical evaluation><pressure><proto-oncogene protein c-erbB-1><receptor><resistance mechanism><resistant><resistant mechanism><response><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><tumor><tumor growth><v-RAF-1 Murine Leukemia Viral Oncogene Homolog 1><v-raf Murine Sarcoma Viral Oncogene Homolog B1>