Lecture 15: Targeted therapies II

Question 1

Three key strategies for targeted
therapies against cancer:

Answer 1

• Monoclonal antibodies
• Small molecule tyrosine kinase
  inhibitors
• Antibody-drug conjugates (ADCs)

Question 2

Drugging the undruggable – p53

Answer 2

• TP53 is the most commonly mutated gene in cancer
• Tumour suppressor
• Mutations are spread out across the gene
• Drugging strategy – changing mutant conformation to
  wild-type conformation
• APR246 is the most clinically advanced p53 reactivator
• P53 W/T can also be used as a therapeutic strategy by
  inhibiting MDM2 binding (MDM2 increases the
  degradation of p53) – increases p53 protein levels

Question 3

Drugging the undruggable - KRAS

Answer 3

• KRAS is an oncogene that is mutated in about 25%
  of all cancers
• KRAS encodes a protein called K-Ras which when
  mutated, contributes to the development of cancer
  through pathways that promote growth, proliferation,
  and differentiation
• KRAS is inactive when bound to GDP and active
  bound to GTP. Mutations in KRAS can keep it in this
  active state
• KRAS-mutant cancers have been difficult to treat via
  drugs due to the small size of K-Ras and its lack of
  binding sites

Question 4

KRAS mutations are common in

Answer 4

pancreatic,
colorectal, and non-small cell lung cancers

Question 5

KRAS (G12C) mutant cycle between

Answer 5

active
and inactive, which allows for the opportunity to
lock in the inactive state

Question 6

Sotorasib was the first KRAS (G12C) inhibitor
approved, adagrasib later also received
approva

Answer 6

New pan-KRAS mutant inhibitors and KRASSOS1/SHP2 disruptors are showing promising
potential

Question 7

5 main intrinsic or molecular subtypes of breast cancer

Answer 7

1. Luminal A (40%) HR+(ER+ AND/OR PR+), HER2-
2. Normal like (2-8%)
   HR+(ER+ AND/OR PR+), HER2-
3. Luminal B (20%)
   HR+(ER+ AND/OR PR+), HER2+/-
4. HER2-ENRICHED (10-15%)HR-(ER-, PR-), HER2+
   5.Triple negative (15-20%)
   HR-(ER- , PR-), HER2-

Receptors: HR: Hormone, ER: Estrogen, PR: Progesterone

Question 8

Pre-clinical cross-comparison of HER2-targeted
TKIs

Answer 8

• Anti-proliferative effect of
  each TKI examined in 115-
  cell line panel
• 25 different tumour tissue
  types
• Neratinib most potent
  across cancer types
• Subtype analysis:
  1. Breast cancer
  2. HER-family altered cancers