Week 7: Cancer and Chemotherapy

CHEM777 - SP26

Why don’t we all have cancer?

Apoptosis

Cell cycle checkpoints

DNA damage repair mechanisms

What accumulates with age?

Driver mutations: Mutations feedback systems degrades

What are the two essential signal transduction pathways for proliferation?

MAPK and PI3K/AKT/mTOR: these pathways are highly regulated in healthy cells

What are the driver mutations that can hyperactivate the pathways, leading to oncogenic cells?

KRAS, BRAF, and PI3K

Gain of Function

Mutation causes protein to be continuously active. Nothing can turn it off (constitutive activity) (KRAS, BRAF)

Loss of Function

Cell cycle arrest/apoptosis inhibition (p53)
Harder to treat
Mutations with the protein that regulates p53

BRAF-mediated signaling plays a role in the initiation, progression, and spread of what cancer?

Melanoma

What does BRAFV600E mean?

Valine to glutamate substitution in the 600 spot

What is PLX4032 (RG7204, Vemurafenib)?

V600 mutant B-Raf inhibitor approved by the FDA for the treatment of late-stage melanoma

Where can drugs bind to block MAPK pathway in cancer?

Drugs can bind to BRAF and MEK kinase

What is difficult for small molecules?

Competitive Kinase Selectivity

What does PLX/RG-7204 inhibit?

It inhibits BRaf by inhibiting the phosphorylation of pMEK and pERK