Cancer Biology: Telomeres and Immortality

Objectives

• 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

Enabling Replicative Immortality

• 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).

Receptor Families Involved in Cancer

• 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 (Epidermal Growth Factor Receptor)

• 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

Targeting EGFR

• 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.

EGFR Mutations and Cancer

• 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

EGFR Resistance to Drugs

• 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

Steroid Hormone Receptors

• 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