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Principal Investigator: Robert Kortum
Organization: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
Fiscal Year: 2024
Award: $331,394
Funding agency: National Cancer Institute
Project Summary/Abstract PI: Kortum, Robert L.
Our data show that RTK−SOS1/2−WT RAS signaling is a critical therapeutic target in RAS-mutated cancers.
Our objective is to differentiate between those RAS-mutated cancers in which inhibiting RTK−SOS1/2−WT
RAS−effector signaling should be part of an overall effective therapeutic strategy.
Direct RAS inhibition as a monotherapy is not effective long-term. RAS proteins show differential activation of
RAF and PI3K pathways: HRAS potently activates PI3K but poorly activates RAF, whereas KRAS potently
activates RAF but poorly activates PI3K. Because of these differences, inhibiting mutant RAS will not effectively
inhibit both the RAF and PI3K pathways. Further, similar to MEK inhibition, mutant RAS inhibition relieves
negative feedback controls leading to rapid hyperactivation of RTK−WT RAS signaling. A more comprehensive
understanding of the interplay between mutant RAS and RTK−WT RAS signaling is essential to developing
rational therapeutic approaches to treat RAS-mutated cancers.
We found inhibition of RAS effectors activated poorly by mutant RAS synergizes with and limits resistance to
mutant HRAS and KRAS inhibitors. The mutant HRAS inhibitor tipifarnib blocks PI3K signaling and synergizes
with MEK inhibitors; covalent KRASG12C inhibitors block MEK signaling and synergize with PI3K inhibitors. We
also found that the RASGEFs SOS1 and SOS2 have unique and overlapping functions that promote mutant
RAS-driven transformation. SOS1 is critical for mutant RAS activation and SOS1 inhibition augments the
efficacy of mutant RAS inhibitors. RTK−SOS2−PI3K signaling protects cells from anoikis and mediates mutant
KRAS-driven transformation depending on the PI3K mutational status. SOS2 KO synergizes with MEK inhibitors
only in PPIK3CA WT cells, whereas SRC inhibitors synergize with MEK inhibitors only in PIK3CA-mutated cells
as was previously reported. These observations suggest the hypothesis that inhibiting RTK−SOS1/2−WT
RAS−effector signaling will impair resistance to, and augment, current therapeutics targeting mutated RAS or
downstream RAS effectors. We will test this hypothesis with the following Aims:
This proposal elucidates the molecular mechanisms through which SOS1/2−WT RAS signaling drives
transformation of cancers harboring specific mutant RAS isoforms. We perform studies using a combination of
defined genetic model systems and more cancer-relevant systems including CRISPR-modified human cancer
cell lines, xenograft studies, and studies using GEMM models to: Determine how WT RAS isoform signaling
cooperates with oncogenic RAS to promote oncogenic transformation. Characterize the role of SOS1 in
mutant RAS-driven proliferation and transformation, both independently and in combination with SOS2.
Establish SOS2 and SRC as therapeutic targets in patient-derived colon cancer organoids based on
KRAS and PIK3CA mutation status. Our findings will inform novel therapeutic approaches for eradicating
subsets of RAS-mutated tumors with genotype-dependent precision.
Terms: <1-Phosphatidylinositol 3-Kinase><Anoikis><Assay><Binding><Bioassay><Biologic Models><Biological Assay><Biological Models><C-K-RAS><CRISPR><CRISPR/Cas system><Cancer cell line><Cancers><Cell Body><Cell Communication and Signaling><Cell Function><Cell Line><Cell Physiology><Cell Process><Cell Protection><Cell Signaling><Cell Survival><Cell Viability><CellLine><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Colon Cancer><Colon Carcinoma><Cytoprotection><Data><Dependence><Drug Synergism><Drugs><Feedback><GEM model><GEMM model><Genetic Alteration><Genetic Change><Genetic Models><Genetic defect><Genetically Engineered Mouse><Genotype><H-ras><H-ras Gene><H-ras Oncogene><HRAS><HRAS gene><HRAS1><Harvey Rat Sarcoma Viral Oncogene Homolog><Heterograft><Heterologous Transplantation><Human><Impairment><Individual><Intracellular Communication and Signaling><Isoforms><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Knock-out><Knockout><MEK inhibition><MEKs><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Model System><Modern Man><Molecular><Molecular Interaction><Mutate><Mutation><Oncogene K-Ras><Oncogenesis><Oncogenic><Organoids><PI-3 Kinase><PI-3K/AKT><PI3-Kinase><PI3CG><PI3K-Alpha><PI3K/AKT><PI3KGamma><PI3k><PIK3><PIK3-Alpha><PIK3CA><PIK3CA gene><PIK3CG><PIK3CG gene><Pathway interactions><Patients><Pharmaceutical Preparations><Phosphatidylinositol 3-Kinase><Phosphatidylinositol 3-Kinase, Catalytic, 110-kD, Alpha><Phosphatidylinositol 3-Kinase, Catalytic, Alpha><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Pre-Clinical Model><Preclinical Models><Proliferating><Protein Isoforms><PtdIns 3-Kinase><RAS genes><RAS inhibition><RASH1><RASK2><Ras Inhibitor><Ras/Raf><Reporting><Research><Resistance><Role><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><Structure><Subcellular Process><System><Testing><Therapeutic><Therapeutic Intervention><Tipifarnib><Toxic effect><Toxicities><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Xenograft><Xenograft procedure><Xenotransplantation><biobank><biological signal transduction><biorepository><cancer cell><cancer in the colon><cultured cell line><cytoprotective><drug/agent><genetically engineered mouse model><genetically engineered murine model><genome mutation><in vivo><inhibitor><intervention therapy><malignancy><mutant><mutation status><mutational status><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><p110-Alpha><pathway><pharmacologic><pre-clinical trial><preclinical trial><predict responsiveness><predicting response><prevent><preventing><ras Gene Products><ras Proteins><reconstitute><reconstitution><resistance to therapy><resistant><resistant to therapy><social role><synergism><targeted agent><therapeutic resistance><therapeutic target><therapeutically effective><therapy resistant><treatment resistance><tumor><tumorigenesis><v-Ha-RAS Harvey Rat Sarcoma Viral Oncogene Homolog><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog><xeno-transplant><xeno-transplantation>