L16. Anticancer II Flashcards
EGFR
- stimulation by ligands
- receptor dimerization
- activating tyrosine kinase activity
- downstream signalling
- increase proliferation, metastasis ..
drugs used to target EGFR:
- prevent ligand binding to EHGR thus inhibiting receptor dimerization
- tyrosine kinase inhibitors bind ATP binding site inhibiting EGFR
HER2
- tyrosine kinase receptor
- member of human epidermal growth receptor family
- has to dimerize upon binding to have downstream effects
lapatinib and neratinib
- kinase inhibitors
- cause direct inhibition of downstream tyrosine kinase domain
trastuzumab
- mab
- binds to the dimerization domain outside the receptor
- inhibits HER2 dimerization
- leading to no downstream signaling
- leads to ADCC: immune cells recognize cancer and promote the killing of the cancer by releasing cytotoxic substances
pertuzumab
- mab
- binds to the dimerization domain outside the receptor
- inhibits HER2 dimerization
- leading to no downstream signaling
- leads to ADCC: immune cells recognize cancer and promote the killing of the cancer by releasing cytotoxic substances
> can be used with trastuzumab since they both binds to a diff portion leading to a synergistic effect
HR+/HER2-
- most common type of breast cancer
- easy to treat
- treat it with endocrine therapy: aromatase inhibitors of SERDs ++ CDK4/6 inhibitors
> in pre-menopausal women, ovarian suppression/ablation is necessary
HR-/HER2-
- worst prognosis
- no tx found so we treat with chemotherapy
HR+/HER2+
- treat with combination therapy: trastuzumab (with or without pertuzumab) + endocrine therapy/anti-hormone tx
HR-/HER2+
least common type of breast cancer
- treat with trastuzumab (with or without pertuzumab) + chemotherapy
tamoxifen
- SERM that blocks estrogen receptors in breasts
- estrogen receptor
recognizes tamoxifen -> ER dimerizes -> ER binds to recognition elements on DNA -> altered gene transcription - tamoxifen acts as an antagonist in breast tissue
- it is metabolized into 4-hydroxytamoxifen and endoxifen by CYP2D6 and CYP3A4/5
aromatase inhibitors
- in post-menopausal women, they continue to produce low levels of estrogen
- testosterone and androstenedione are converted to estradiol and estrogen via enzyme aromatase
- aromatase inhibitors will inhibit the enzyme aromatase which will reduce estrogen levels inhibiting the growth of cancer cells
fulvestrant
- selective estrogen receptor downregulation
- pure ER antagonist with no agonist activity
- downregulates and destroys ER receptors
- fulvestrant has a long side chain that will cause the ER dimerization to be sterically hindered which will destroy ER receptor
CDK6 and CDK4 inhibitors
CDK4/6 usually promote cell cycle entry by blocking repressor retinoblastoma and cell progression from G1 phase to S phase
synthetic lethality
combination of two non-lethal mutations resulting in cell death while each mutation alone is not lethal
cancer immunotherapy
principle of activating and enhancing the body’s immune system to recognize and destroy cancer cells
CTLA4 and PD1
both expressed on tumour cells that will help cancer evade the immune system
checkpoint inhibitors
antibodies against CTLA4 and PD1 will inhibit them and will make the immune cells recognize the cancer cells to attack them
–> targeting them will enhance the immune system’s ability to recognize and attack cancer cells
