Lecture 5 : Cancer therapy and innate immunity

What is synthetic lethality?

• Combined loss of two genes → cell death; loss of either alone → viability

• Exploits pathway redundancy to target specific vulnerabilities

How is synthetic lethality used in cancer therapy?

• Target a pathway compensating for a tumour’s existing defect → selective cancer cell kill

• Minimises toxicity to normal cells that retain both pathways

Why are DNA repair defects good synthetic-lethal targets?

Tumours often have specific repair deficiencies; inhibiting the backup pathway causes catastrophic DNA damage

What was the first clinical demonstration of DNA repair synthetic lethality?

PARP inhibitors (PARPi) in BRCA1/BRCA2- deficient cancers (e.g. olaparib)

What is the mechanism of PARP inhibitor killing in BRCA-deficient cells?

PARP inhibition prevents SSB repair → SSBs convert to DSBs at replication forks → HR-deficient (BRCA-) cells cannot repair DSBs → cell death

What is Olaparib?

A PARP inhibitor used to treat BRCA-mutant ovarian, breast and other cancers; clinical success established proof-of-prininciple

Key clinical considerations when using PARPi?

Tumour BRCA/HR status, potential resistance mechanisms, hematologic toxicity, and combination treatment risks

How can tumours develop resistance to PARP inhibitors?

Restoration of HR (reversion mutations), drug efflux, PARP1 mutations, or upregulation of alternative repair pathways

What is a micronucleus?

Small,extranuclear chromatin-containing body formed from missegregates chromosomes or chromosome fragments

Why are micronuclei important in genome instability?

Their rupture exposes DNA to the cytosol, producing abnormal DNA structures that trigger danger sensors

What is cGAS and what does it sense?

cGAS is a cyctolic DNA sensor that detects double-stranded DNA in the cytosol (including ruptured micronuclei)

What pathway does cGAS activate after sensing cytosolic DNA?

cGAS synthesises cGAMP → activates STING on the ER → downstream signalling → type 1 interferon and ISG incuction

What is STING and its role?

Stimulator of interferon genes, is an adaptor that transduces cGAMP signals to induce innate immune responses and ISGs

What are ISGs?

Interferon-stimulated genes induced by type 1 IFN signalling; encode antiviral, pro-inflammatory and DNA damage-responsive factors

How does sensing of ruptured micronuclei link genome instability to innate immunity?

Cytosolic DNA from ruptured micronuclei activates cGAS-STING → type 1 IFN/ISG responses → inflammation or anti-tumour immunity

How can cGAS-STING activation affect cancer?

Can promote anti-tumour immune responses (good) or drive shronic inflammation/immune suppression and tumour progression (bad), depending on context

How does DNA damage contribute to auto-inflammation?

Persistent DNA leakage or unrepaired damage chronically activates cGAS-STING and IGS→ sterile inflammation and auto-inflammatory disease

How can knowledge of DNA repair and innate sensing improve therapy?

Combine DNA-damaging agents or repair inhibitors with immune modulators to boost anti-tumour immunity or avoid auto-inflammatory toxicity; patient stratification by repair/immune status

What safety concerns arise when exploiting DNA repair therapeutically?

Off-target toxicity (e.g. neurotoxicity), secondary malignancies, and exacerbation of auto-inflammation - requiring careful drug selection and monitoring

Practical steps to translate DNA-repair biology into better patient care?

Test tumours for repair defects (biomarkers), choose targeted inhibitors (e.g. PARPi) or combinations, monitor immune activation (cGAS/STING/IGS markers), and tailor therapy to minimise toxicity