Molecular basis of endocrine therapy!

Question 1

How does oestrogen interact with ER-1?

Answer 1

Ligand binds in hydrophobic pocket; stabilises active conformation; allows coactivators such as GRIP1 to bind. Chaperones then dissociate and receptor dimerises before interacting with the essentially palindromic ERE DNA sequences via DNA binding domain (DBD); leads to transcription of genes including BCL-2 (antiapoptosis) and VEGF.

Question 2

Fulvestrant?

Answer 2

Full oestrogen agonist. Can be second line therapy in select situations. Can be used after relapse or after ESR1 mutation.

Question 3

Where does tamoxifen bind?

Answer 3

Binds to hydrophobic LBD where oestrogen binds, but the tail of the molecule stops crucial coactivators binding.

Question 4

Three ways to get tamoxifen resistance?

Answer 4

Interactions with other drugs e.g. tamoxifen and paroxetine/fluoxetine. Tumour heterogeneity i.e. dominant clone no longer addicted to pathway. Or activating ESR1 mutations means inhibition is resisted. If this is the case, can give fulvestrant or raloxifene (another SERM) but not an AI if activating ESR1.

Question 5

Relapse and mTOR signalling?

Answer 5

Relapse on AI/tamoxifen is associated with increased mTOR signalling. Can therefore give mTOR inhibitor e.g. everolimus along with exemestane (steroidal AI).