4.4

Question 1

What is the normal role of RTK signalling?

Answer 1

To mediate controlled cell proliferation, migration, survival, and differentiation.

Question 2

What happens when RTK signalling becomes dysregulated?

Answer 2

Constitutive activation leads to cancer and other diseases due to uncontrolled growth/migration.

Question 3

What non-cancer diseases are linked to tyrosine kinase dysfunction?

Answer 3

Diabetes (insulin receptor), skeletal disorders (FGFR1–3), inflammation (PDGFR and others).

Question 4

What is the normal role of FGFR3 in bone growth?

Answer 4

It inhibits proliferation of chondroblasts to regulate long bone growth.

Question 5

What causes achondroplasia?

Answer 5

A gain-of-function FGFR3 mutation (G380R) leading to early chondrocyte differentiation.

Question 6

Name other FGFR3 mutation-related disorders.

Achondroplasia

Answer 6

Hypochondroplasia (N540K), coronal craniosynostosis (P250R).

Question 7

Name the hallmarks of cancer.

Answer 7

Uncontrolled proliferation, evasion of suppressors, apoptosis resistance, immortality, angiogenesis, metastasis, immune evasion.

Question 8

How are RTKs involved in cancer hallmarks?

Answer 8

Drive proliferation, angiogenesis, invasion, immune evasion.

Question 9

What % of human cancers are virus-associated?

Answer 9

~10–20%.

Question 10

Name three major cancer-causing viruses.

Answer 10

EBV (lymphoma), HPV (cervical/HNSCC), HBV/HCV (liver cancer).

Question 11

What did early viral cancer studies lead to?

Answer 11

Discovery of tyrosine kinases like v-src and v-Abl.

Question 12

What are viral oncogenes?

Answer 12

Mutated versions of normal host proteins that hijack pY-based signalling.

Question 13

Give examples of viral oncogenes and their targets.

Answer 13

v-Sis (PDGF), v-ErbB (EGFR), v-Src (Src), v-Akt (Akt), v-Crk (Crk), v-Myc (transcription).

Question 14

List 5 mechanisms of TK dysregulation in cancer.

Answer 14

1) Viral hijacking, 2) Autocrine ligand expression, 3) Chromosomal translocations, 4) Gene amplification, 5) Gain-of-function mutations.

Question 15

Give an example of autocrine RTK signalling in cancer.

Answer 15

TGFα and EGFR in breast cancer.

Question 16

Give examples of RTK fusion proteins due to translocations.

Answer 16

BCR-Abl (CML), FGFR3 (bladder, myeloma), ALK (NSCLC).

Question 17

Give examples of RTK gene amplification.

Answer 17

HER2 (breast), EGFR (GBM).

Question 18

Give examples of activating TK mutations.

Answer 18

c-Kit (GIST), EGFRvIII (GBM), EGFR (NSCLC).

Question 19

What RTKs are linked to NSCLC?

Answer 19

ALK/ROS1 fusions, EGFR/FGFR1/PDGFRA mutations, HER2 amplification.

Question 20

What does EGFR dysregulation cause?

Answer 20

Multiple carcinomas, particularly epithelial (lung, brain, etc.).

Question 21

What are 4 EGFR dysregulation mechanisms?

Answer 21

1) Viral hijack, 2) Excess ligand, 3) Gene amplification, 4) Activating mutations.

Question 22

What role does HER2 play in breast cancer?

Answer 22

Amplification (up to 50 copies) drives poor-prognosis, HER2+ breast cancer.

Question 23

What causes GIST (gastrointestinal stromal tumour)?

Answer 23

Activating mutations in c-Kit (80%) and PDGFRα (20%).

Question 24

What is VEGF’s role in cancer?

Answer 24

Promotes angiogenesis in hypoxic tumours.

Question 25

What VEGFR is critical for tumour angiogenesis?

Answer 25

VEGFR2 (responds to VEGF-A).

Question 26

What drug targets VEGF-A?

Answer 26

Bevacizumab (anti-VEGF antibody).

Question 27

What translocation creates BCR-Abl?

Answer 27

t(9;22) joins BCR (chr 22) and c-Abl (chr 9).

Question 28

What cancer is caused by BCR-Abl?

Answer 28

Chronic Myeloid Leukaemia (CML).

Question 29

What role does c-Src play in cancer?

Answer 29

Its overactivation correlates with malignant progression in various cancers.

Question 30

What cells in the tumour microenvironment support cancer?

Answer 30

Tumour-associated macrophages (TAMs), fibroblasts, some T cells.

Question 31

What do TAMs do?

Answer 31

Promote cancer growth, angiogenesis, and suppress immune responses.

Question 32

What are two types of TK-targeting therapies?

Answer 32

1) Humanised antibodies (extracellular), 2) Small molecule inhibitors (intracellular).

Question 33

How do these therapies work?

Answer 33

Block aberrant proliferation/survival signals from TKs.

Question 34

What was the first non-specific TKI?

Answer 34

Staurosporine (1980s).

Question 35

What major TKIs were developed in the 2000s?

Answer 35

Imatinib (BCR-Abl), Trastuzumab (HER2).

Question 36

What does Imatinib target?

Answer 36

BCR-Abl, c-Kit, PDGFRα.

Question 37

How does Imatinib treat CML?

Answer 37

Inhibits BCR-Abl, inducing leukaemic cell apoptosis.

Question 38

Why is Imatinib effective for GIST?

Answer 38

It also inhibits c-Kit and PDGFRα mutations driving GIST.

Question 39

What is Trastuzumab?

Answer 39

A humanised antibody targeting HER2’s extracellular domain.

Question 40

What cancer is it used for?

Answer 40

HER2+ breast cancer.

Question 41

What is Pertuzumab?

Answer 41

An anti-HER2 antibody that binds a different epitope; used in combination.

Question 42

What are next-gen HER2 therapies?

Answer 42

Antibody-drug conjugates like Trastuzumab-emtansine (T-DM1).

Question 43

Why are single-target TKIs less effective in solid tumours?

Answer 43

Due to genetic complexity and pathway redundancy.

Question 44

What causes resistance to TKIs?

Answer 44

De novo resistance or secondary mutations (e.g., EGFR T790M).

Question 45

What does Staurosporine target?

Answer 45

Over 250 kinases; highly non-selective.

Question 46

What is Dasatinib?

Answer 46

A second-gen multi-target inhibitor for BCR-Abl, Src family kinases, and more.

Question 47

What is Sunitinib used for?

Answer 47

Metastatic melanoma, renal cell carcinoma; inhibits VEGFR, PDGFR, FLT3.

Question 48

What is Erlotinib?

Answer 48

An EGFR TKI used in NSCLC that also hits some S/T kinases.

Question 49

Name antibodies targeting the EGFR family.

Answer 49

Cetuximab (EGFR), Trastuzumab & Pertuzumab (HER2).

Question 50

Name kinase inhibitors targeting the EGFR family.

Answer 50

Gefitinib, Erlotinib (EGFR); Lapatinib, Neratinib (HER2).

Question 51

What % of common cancer patients receive targeted therapy (as of 2020)?

Answer 51

Less than 25%.

Question 52

What limits further precision treatment?

Answer 52

Undruggable targets (e.g., K-Ras), or mechanisms not yet fully understood.