Proto-oncogenes and Oncogenes

Proto-oncogenes

• group of mutated genes that cause normal cells to become cancerous due to uncontrolled growth

Oncogenes

cellular gene that becomes dysfunctional due to mutations, overexpression, and/or fusion with another gene

mutated proto-oncogene that becomes cancerous

Consequences of oncogenes

• increased activity

• gene amplification (increased levels)

• chromosomal translocation (loss of regulation)

Src oncogenes

• switches from inactive to active state through control of its phosphorylation state

• phosphorylation stage is regulated by the CSK (c-Src-kinase)

Three main domaines of Src

• SH2 - Src homology 2

• SH3 - Src homology 3

• kinase domain

Central role of Src kinase in cells

Src transmits signals from growth factor receptors, integrins, and G-protein coupled receptors which aids in functions such as

• Cell Proliferation and Survival:

  • Src activates pathways like RAS/MAPK and PI3K/AKT, promoting cell cycle progression and inhibiting apoptosis.

• Cell Adhesion and Migration:

  • Src regulates focal adhesions and actin cytoskeleton remodeling, controlling how cells attach, move, and spread.

  • Important in wound healing, development, and cancer metastasis.

• Angiogenesis:

  • Src influences the formation of new blood vessels by regulating VEGF signaling and endothelial cell functions.

Viral fossils in human genome

• human genome contains ~8% viral genes

• may boost host immunity which can:

  • block viral infection

  • recognize specific invaders

  • converts RNA into DNA when retrovirus infects

HPV

Human Papilloma Virus

• non-eveloped, ds, circular DNA virus in the Papillomaviridae family

• common infection

• results in epithelial lesions and cancers at primarily cutaneous and mucosal surfaces

• inactive in early infection but keeps the cell from entering a resting (G0) state to dysregulate cell cycle

Risk Factors of HPV

• sexual activity

• age of first sexual intercourse

• number of sexual partners

• oral contraceptives for > 5 years

• smoking

• radiation/UV light

• betel nut chewing

E2 in HPV

regulates transition from early to late phase genes and allows the virus to continue virion production in HPV-driven lesions

EGFR role in virus entry

EGFR activates the cell and viruses take advantage of that and use that system to aid in attachment, internalization, and triggering signaling pathways that facilitate their entry and replication

EGFR function

• receptor tyrosine kinase

• activation of this GF allows for the downstream activation of Ras/MAPK and PI3K-PKB pathways which regulate gene function and cell proliferation

Why is it hard to target EGFR as a cancer therapy?

receptor tyrosine kinase are all kind of interlinked and related

we stop EGFR but then it “talks” to another RTK which can restart the issue of the genes for cell proliferation being overexpressed

Mechanisms for mediating the abnormal RTK function activation

• gain of function

• genomic amplification

• chromosomal rearrangement

• autocrine activation

TKI strategies

Tyrosine Kinase Inhibitor

• block the intrinsic kinase domain of the receptor (an example would be small molecule inhibitors that can inhibit the ATP binding site e.g. imatinib)

Tyrosine Kinase Receptors - Issues for treatment

If we target a specific gene (e.g. HER2/neu in breast cancer) another gene could be using the same pathway to mediate something essential (e.g. lung expansion) which would also be inhibited

TKIs development

1st gen - gefitinib and erlotinib

2nd gen - afatinib and dacomitinib

3rd gen - osimertinib, olmutinib and rociletinib

• if any cells remain after the use of any of the TKIs, they become resistant and replicate and mutate so they can surpass it and so another generation is needed

Methods for detection of HER2/neu

• immunohistochemistry

  • biopsy tissue staining with monoclonal antibody performed under standardized conditions

• flurescent in situ hybridisation (FISH)

  • detects gene expression

  • more sensitive than IHC

• enzyme-linked immunosorbent assay (ELISA)

  • detects cleavage product in serum

Herceptin

Trastuzumab

• binds to HER2 and blocks it’s activity

• supresses the intracellular signalling pathway

• inhibits cell cycle arrest and mediates antibody-dependent cell-mediated cytotoxicity

MOA of Trastuzumab

• doesnt kill cells

• slows them down and hopes the immune system recognises it as foreign and harmful and engages to eliminate it

Future directions for Cancer therapy

Antibodies are being conjugated for cells to either cause the cancer cell to kill itself or trigger the immune system to kill it

Ras as an anti-cancer target

• Ras has a fatty acid modification which attaches it to the membrane

• inhibitors of this modifications have been developed which have promise e.g. farnesyl transferase inhibitors (FTI)

• potential future therapeutic target

Alternative approaches to treating cancer

can try to block to the transcriptional elements that are involved with the production of the proteins involved in cancer e.g. HRas

hard to get them into the cancer cells tho