B8.039 Prework 3: Limitations of Targeted Breast Cancer Therapies (Resistance) Flashcards
what are the limitations of targeted breast cancer therapies
resistance to endocrine therapy affects 30-40% of breast cancer patients
multiple pathways are involved in the development of endocrine resistance
pathway redundancy
ability of a signaling pathway to remain activated, despite being inhibited by a targeted therapy
escape pathways
even if a signaling pathways is inhibited, a cell could recruit an alternate signaling pathways and escape the effects of targeted therapy
pathways reactivation
ability of a cell to reactivate the signaling pathways via mutations within the downstream receptor layer, despite the presence of inhibitory therapy
cross talk between ER and growth factor receptor signaling pathways
drives endocrine resistance
overexpression of Pi3Kt/mTOR
cell is not longer dependent on E for growth and survival
what are ESR1 mutations
mutations in ligand binding domain
make receptor constitutively active, so E not necessary to mediate effect
how common are ESR1 mutations
5% of resistant tumors
mechanisms of resistance to trastuzumab
- enzymatic cleavage of HER2 receptor, so drug has nowhere to bind and pathways remains active
- epitope masking prevents Ab from binding receptor
- activation of downstream signaling pathways > PTEN loss of function/loss of inhibition
how do you overcome endocrine resistance in breast cancer
targeting multiple signaling pathways
importance of CDK4/6
overexpressed in some endocrine resistant tumors
keeps cells progressing through the cell cycle
how to target CDK4/6 with therapy
-ciclib drugs
use in combo with AIs or fulvestrant
mTOR pathway targeting
everolimus
temsirolimus
overcomes trastuzamab resistance mechanisms
