Cancer Biology: Telomeres and Immortality

Study Notes

Understand why cancer cells are immortal
Describe the main receptor signaling pathways in cancers
Describe examples of receptors and their relevance as drug targets
Understand the importance of signal transduction in allowing abnormal proliferation

Telomeres are repetitive nucleotide sequences at chromosome ends
Telomeres protect chromosome ends from fraying
Telomeres shorten with each cell division
Short telomeres cause cell division to stop (senescence)
Telomerase is an enzyme that restores telomeres
90% of cancers activate Telomerase
Telomerase is a reverse transcriptase using RNA templates
Telomerase adds DNA repeats in germ cells and embryonic stem cells
Cells expressing telomerase have stable telomere length, e.g., germline cells and embryonic stem cells
Pluripotent stem cells control telomere activity
Normal cells lack telomerase
Without telomerase, telomeres shorten until the cell is unable to divide (senescence)
If checkpoints are disrupted (like P53 loss), cells may bypass senescence and keep dividing until crisis and death
Cancer cells may activate telomerase (or use another method called alternative telomere lengthening (ATL).

Receptors include receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and steroid hormone receptors
Receptor activation often leads to gene expression changes
Examples of receptors include EGFR (epidermal growth factor receptor) which senses growth signals
EGFR is pro-proliferative and pro-survival

EGFR senses growth signals
EGFR is pro-proliferative and pro-survival
EGFR activation leads to dimerization
EGFR dimerization causes receptor phosphorylation
EGFR activation leads to intracellular signaling pathways (including PI3K, AKT, RAS, RAF, ERK, MEK)
EGFR activation can stop apoptosis
EGFR activation can stimulate protein synthesis

Drugs like Pertuzumab, Cetuximab, Trastuzumab, Gefitinib, Erlotinib, Lapatinib, and Afatinib target EGFR
These drugs inhibit or block EGFR's activity
Specific drugs target different aspects of EGFR function
Variations of targeting drugs result in different mechanisms of action impacting different pathways.

Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers
EGFR is often overexpressed in NSCLC (in 60%)
Activating mutations can arise within the catalytic tyrosine kinase domain of the EGFR protein
Short in-frame deletions (e.g., E746-A750del) in exon 19 lead to loss of amino acids
These deletions increase tyrosine kinase activity
Mutations can impact EGFR receptor function in different ways

T790M mutation arises in the ATP-binding site
This mutation increases the affinity of EGFR for ATP
This reduces the affinity of competitive inhibitors like gefitinib and erlotinib
T790M mutation commonly results in resistance to gefitinib and erlotinib

The steroid hormone receptor superfamily includes receptors for estrogen, androgen, progesterone, and retinoic acid
These receptors are nuclear receptors
They bind to DNA to regulate gene expression
Examples of steroid hormone receptors include estrogen receptor and androgen receptor