Signalling pathways and targeted therapies (solid tumors) / Molecular oncology II Flashcards
signal transduction
converting signals into cellular processes
cell surface receptors
G-protein coupled receptors, enzyme-coupled receptors (RTKs), ion-channel coupled receptors
intracellular receptors
transcription factors, hormone receptor, DNA
primary messenger
signal
what characterizes a receptor?
specificity
What are cellular responses in signal transduction?
altered gene expression, protein function (migration, proliferation, differentiation, apoptosis)
what is a second messenger?
low molecular weight intracellular signaling molecules (from plasma membrane to cell interior)
examples of second messengers
cAMP, cGMP, DAG, IP3, PIP3, Ca2+ NO, O2-
protein kinases
add phosphate to -OH of tyrosine/serine/threonine residues of target protein
phosphatases
remove phosphate
GTPase proteins
GAP: GTPase activating protein
GEF: Guanine nucleotide exchange factor
example of trimeric G-proteins
GPCR (G-protein-coupled receptor)
example of monomeric G-proteins
e.g. Ras
examples for MAPK signalling pathways
EGFR, Insulin receptor, FGFR
how do MAPK signaling pathways regulate essential cellular processes?
GEF-SOS links to Ras (GDP-release), GTP binds, active Ras, activates Raf (MAPKKK), phosphorylates MAPKK, phosphorylates MAPK, cytoplasmic targets, activates transcription factors in nucleus
descibe PI-signaling!
phosphoinositide-3-kinase catalyzes PI4,5,bisphosphate (PIP2) to PI3,4,5-triphosphate (PIP3) which activates AKT (protein kinase B), modifies multiple downstream pathways
how is signaling regulated and connected?
- negative feedback loops, incoherent feedback loops
- receptor specifity, number, affinity, phosphorylation, endocytosis
- degradation of 2nd messenger, phosphatases
- subcellular localization of signaling molecules & scaffolding
- cell/tissue type
- signal strength/duration
- cross-talk and integration (fine tuning)
how are intracellular signaling pathways related to cancer?
- constitutively active Ras
- Raf-mutation
- constitutively active RTK, overexpression
chemotherapeutics
induce DNA lesions (affects rapidly dividing cells more)
targeted therapy
block a specific signaling pathway e.g PARP inhibitors, HDAC inhibitors
immune therapies
help immune system to recognize cancer
how can the TME (tumor microenvironment) influence cancer growth and immunogenicity?
fibroblasts, tumor infaltring/associated macrophages (TIM/TAM), tumor-associated dendritic cells, cytokines, density, metabolic state, senescent cells, paracrine effects
give examples of immunotherapy
cytokines, checkpoint inhibition, antibodies, vaccination, Car-T
how is the dysregulated EGFR signalling in breast cancer inhibited?
anti-HER2-therapy: combination between anti-HER2 and EGFR-inhibition
how is the dysregulated EGFR signalling in lung cancer inhibited?
Pan-EGFR-inhibition, or downstream inhibitors such as BRAFi and MEKi
why are second messengers so efficient and widely present?
- strong signal amplification
- recycling of receptor ligands
- no need for signal to enter the cell directly
- multiple molecular events for signal transmission: better regulation
