Cancer genetics Flashcards
3 things that lead to more mutations in cancer cells vs normal cells
proliferation, loss of p53, and genomic instability
List some things that result from clonal expansion in cancer cells
increased survival, proliferation, tumor propagating potential, metastasis, chemotherapy resistance
Which has more genomic instability and CNVs, localized or metastatic cancers?
metastatic
What is the “magic bullet”?
Gleevec (imatinib) that treats blood cancer
What do 95% of CML patients have?
philadelphia chromosome
Hybrid Bcr-Abl protein results in constitutive activation of what?
Tyrosine Kinase of abl
What does Gleevec inhibit?
Tyrosine kinase of abl
Why is Gleevec so effective?
Normal cells have non-abl tyrosine kinases, which allows them to continue to function even when the abl TKs are inhibited, while the cancerous cells only have the abl-fusion TKs
What is another example of chromosomal translocation gene fusion inhibitor anti-cancer therapy?
Larotrectinib, an NTRK inhibitor, for solid tumors with NTRK gene fusions in prostate cancers
These kinds of chemo drugs add an alkyl group to DNA, cause DNA damage, and stop DNA replication
Alkylating agents and platinum based drugs (cisplatin, carboplatin)
These chemo drugs disrupt microtubule functions
Taxanes
This type of chemo drugs inhibit specific targets within cancer cells
targeted therapy
This anti-cancer treatment cannot differentiate btw normal and cancer cells, so it is toxic to all cells, especially rapidly proliferating cells
chemotherapy
Proteasome inhibitors and tyrosine kinase inhibitors are examples of what class of drugs?
small molecule inhibitors
These drugs bind to intracellular kinase domain and act as competitive inhibitor of ATP binding
Tyrosine kinase inhibitors
These drugs target receptors on the surface of cancer cells to prevent receptor activation
Antibody drugs (usually monoclonal abs)
these mutations are the primary force for promoting cancer formation and progression, and caused by overexpression, amplification, or mutation
Driver mutations
Examples of Driver Mutations
BCR/ABL, ALK fusion gene, EGFR, HER-2, BRAF, Ras, Myc
How are cancers often classified for targeted therapies in recent years?
biomarker genetic testing to determine “driver mutations”
This gene family is often mutated or amplified in lung and breast cancer
HER/EGFR family
The 2 major signaling pathways for EGFR
PI3K/AKT and kRAS/BRAF/MEK/ERK
This mutant of HER resembles a ligand-activated state
HER2
This class of drugs enters cells and inhibits the intracellular portion of EGFR
TKIs, tyrosine kinase inhibitors (specific for EGFR), including erlotinib and gefitinib
This class of drugs does NOT enter a cell and blocks EGFR surface proteins
anti-EGFR mAb drugs, including cetuximab, panitumumab, and nimotuzumab
Which targeted EGFR therapy often results in resistance
TKIs
What do you need for EGFR with a T790M mutation?
a 4th generation TKI: osimertinib
3 things that confer resistance to anti-EGFR therapies
Met receptor activation, PI3K mutation, or Ras mutation
Activating kRas mutations are found in which type of cancer?
metastatic colorectal cancer
3 methods to detect HER2
immunohistochemistry, PCR, and FISH
Mechanism of mAb therapy for Her2
prevents HER2 dimerization, downregulates receptor by endocytic destruction, and induce ADCC by NK cells and macrophages
What are some of the ways to stratify BCa patients based on molecular markers?
Hormone receptors (estrogen or progesterone receptors), HER2 status, or triple negative for all 3 (for which you just gotta use chemo and radiation)
This gene is involved in dsDNA damage repair and mutations result in breast cancer
BRCA1/2
How do PARP inhibitors work to treat BRCA mutant cancers?
It inhibits PARP, which would normally repair single stranded DNA breaks. Without PARP, double stranded breaks occur. Cells with the BRCA1/2 normal will be repaired and survive, while the mutant lines will die.
How does the cancer immune checkpoint work?
it’s an intrinsic mchanism that prevents over-activation of T cells
How do immune checkpoint anti-cancer therapies work?
target antibodies to PD-1 or PD-L1 which restores the anti-tumor function on T cells. Cancer cells can cause PD-1 to bind with PD-L1 and inactivate the T cell which allows cancer cells to avoid immune attack and proliferate.
