Signalling pathways and targeted therapies (solid tumors) / Molecular oncology II

Question 1

signal transduction

Answer 1

converting signals into cellular processes

Question 2

cell surface receptors

Answer 2

G-protein coupled receptors, enzyme-coupled receptors (RTKs), ion-channel coupled receptors

Question 3

intracellular receptors

Answer 3

transcription factors, hormone receptor, DNA

Question 4

primary messenger

Answer 4

signal

Question 5

what characterizes a receptor?

Answer 5

specificity

Question 6

What are cellular responses in signal transduction?

Answer 6

altered gene expression, protein function (migration, proliferation, differentiation, apoptosis)

Question 7

what is a second messenger?

Answer 7

low molecular weight intracellular signaling molecules (from plasma membrane to cell interior)

Question 8

examples of second messengers

Answer 8

cAMP, cGMP, DAG, IP3, PIP3, Ca2+ NO, O2-

Question 9

protein kinases

Answer 9

add phosphate to -OH of tyrosine/serine/threonine residues of target protein

Question 10

phosphatases

Answer 10

remove phosphate

Question 11

GTPase proteins

Answer 11

GAP: GTPase activating protein
GEF: Guanine nucleotide exchange factor

Question 12

example of trimeric G-proteins

Answer 12

GPCR (G-protein-coupled receptor)

Question 13

example of monomeric G-proteins

Answer 13

e.g. Ras

Question 14

examples for MAPK signalling pathways

Answer 14

EGFR, Insulin receptor, FGFR

Question 15

how do MAPK signaling pathways regulate essential cellular processes?

Answer 15

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

Question 16

descibe PI-signaling!

Answer 16

phosphoinositide-3-kinase catalyzes PI4,5,bisphosphate (PIP2) to PI3,4,5-triphosphate (PIP3) which activates AKT (protein kinase B), modifies multiple downstream pathways

Question 17

how is signaling regulated and connected?

Answer 17

• 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)

Question 18

how are intracellular signaling pathways related to cancer?

Answer 18

• constitutively active Ras
• Raf-mutation
• constitutively active RTK, overexpression

Question 19

chemotherapeutics

Answer 19

induce DNA lesions (affects rapidly dividing cells more)

Question 20

targeted therapy

Answer 20

block a specific signaling pathway e.g PARP inhibitors, HDAC inhibitors

Question 21

immune therapies

Answer 21

help immune system to recognize cancer

Question 22

how can the TME (tumor microenvironment) influence cancer growth and immunogenicity?

Answer 22

fibroblasts, tumor infaltring/associated macrophages (TIM/TAM), tumor-associated dendritic cells, cytokines, density, metabolic state, senescent cells, paracrine effects

Question 23

give examples of immunotherapy

Answer 23

cytokines, checkpoint inhibition, antibodies, vaccination, Car-T

Question 24

how is the dysregulated EGFR signalling in breast cancer inhibited?

Answer 24

anti-HER2-therapy: combination between anti-HER2 and EGFR-inhibition

Question 25

how is the dysregulated EGFR signalling in lung cancer inhibited?

Answer 25

Pan-EGFR-inhibition, or downstream inhibitors such as BRAFi and MEKi

Question 26

why are second messengers so efficient and widely present?

Answer 26

• strong signal amplification
• recycling of receptor ligands
• no need for signal to enter the cell directly
• multiple molecular events for signal transmission: better regulation