Cancer Oncogenes as Drug Targets

Week 26 – Cancer Oncogenes as Drug Targets

Finding Key Mutations: Diagnosis and Treatment:

Cancer cells have extensively rewired pathways for growth and survival that underlie the malignant
phenotype. Thus, a key to successful therapy is the identification of critical, functional nodes in the
oncogenic network whose inhibition will result in system failure, that is, the cessation of the
tumorigenic state by apoptosis, necrosis, senescence, or differentiation

Some mutated oncoproteins are frequently associated with specific cancers (Drivers):




Example Tumour Suppressors:




Many Benign Tumours can Become Malignant: Cancer is a Multistep Process:

Colon Cancer:

Normal colonic mucosa  Loss of apc gene (chromosome 5) Promotes DNA replication  Benign
(early) adenoma  Oncogenic mutation of a ras gene, Growth factor independence Benign (late)
adenoma  Loss of p53 gene (chromosome 17) Loss of a gene (possibly dcc) on chromosome 18,
Apoptosis not triggered  Malignant invasive carcinoma

Promotes DNA replication, Growth factor independence, Apoptosis not triggered = Evading growth
suppressors, Sustaining proliferative signalling

Astrocytoma:

Normal tissue  Loss of p53 gene  Low grade tumour  Loss of a cluster of genes on
chromosome 9  Higher grade tumour  Multiplication of gene for epidermal growth factor
receptor (chromosome 7) Loss of one copy of chromosome 10  Most aggressive form of tumour

N.B. Most tumours are genetically unique – may assist personalised medicine

Some genes cause high frequency of altered protein products across tumour types

, Mutation (Genetic) Hotspots in Cancer Genes:

 TP53 tumour suppressor protein is a cell cycle regulator
 At codon 157 in TP53, G-T transversions are frequently seen in smokers’ lung cancers, but
not in never-smokers

Chromosomal (Genomic) Hotspot example:

The Philadelphia Chromosome and BCR-ABL fusion protein in CML

Oncogenes as Small Molecule Drug Targets:

 Some mutations are more dominant/essential than others in inducing and progressing
cancers
 These are attractive targets for drug design and are known as targeted therapies

Imatinib for chronic myelogenous Leukemia targets the tyrosine kinase signal transducer BCL-abl

Breast cancer therapy uses HER2 therapies targeting the Human epidermal growth factor 2
HER-2/neu oncogene

EGFR targeted therapies target Epidermal growth factor (EGFR) mutation in lung cancer and colon
cancer

BRAF inhibitors target BRAF mutations in melanomas

Vitrakvi (Larotrectinib) inhibits tropomyosin receptor kinase (TRK) inhibitor proteins produced by
NTRK fusion genes in multiple cancers

Oncogenes as Monoclonal Antibody (Biologic) Drug Targets:

 Antibodies are glycoproteins that recognise specific antigens
 Produced in vivo by plasma B cells of the adaptive immune system
 A single B cell clone produces one specific antibody (monoclonal antibody/mAb)
 Can be engineered in large quantities against tumour targets
 Direct action by the antibodies can cause ligand blocking and receptor blocking of the
tumour

Antibody Drug Conjugates:

 Combining mAb specificity for tumour antigen makes delivering cytotoxic compounds
directly to tumour cells less toxic
 Antibody is internalised to deliver drugs, radionuclide agents
 Cause DNA damage and tumour cell death

Precision (Personalised) Medicine Oncogene Case Studies:

Case Study 1 – Point Mutations/Deletions in the Epidermal Growth Factor Receptor Family of
Proteins

EGFR: A Growth Factor Tyrosine Kinase Receptor:

 Acts via Epidermal growth factor ligand
 EGFR is expressed by the proto-oncogene C-erbB-1 (also known as Her-1 or ErbB-1)
 Family members are overexpressed in many tumour types (e.g., Her2-breast)