Table 2.

Contribution of DNA Damage Repair pathway alterations to Platinum and PARPi resistance.

DNA Damage Repair Pathway	Key Pathway Functions	Key Genes	Effect of Pathway Alterations on Therapeutic Resistance
Homologous Recombination (HR)	Repair of DSBs or stalled replication forks during S and G2 phases of cell cycle	BRCA1, BRCA2, RAD51, HSP90	Reactivation of HR pathway enables repair of DSBs and resolves replisome blocks, promoting cancer cell progression through the cell cycle despite the presence of cytotoxic DNA damage.
Non-Homologous End Joining (NHEJ)	Repair of DSBs during interphase	53BP1	Loss of 53BP1 re-wires NHEJ pathway, reactivating HR independent of BRCA1
Base Excision Repair (BER)	Repair of SSBs and DNA base lesions	PARP-1, XRCC1, Pol β	Functional BER pathway leads to loss of synthetic lethality and PARPi resistance
Nucleotide Excision Repair (NER)	Removes “bulky lesions” which distort the DNA double helix, including intra-strand crosslinks formed by platinum adducts.	ERCC1, XPF	Upregulation of ERCC1 and XPF potentially restores NER function. NER pathway alteration potentially confers sensitivity to platinum, and not PARPi.
Fanconi Anemia (FA)	Removes intra-strand DNA crosslinks, coordinates DNA replication by fine-tuning mitotic checkpoints and replication fork stabilisation	FANCC, FANCD2, FANCA	Mutations in FA pathway genes may have a similar effect to BRCA1 and BRCA2 mutation, in promoting progression of cancer cell through the cell cycle, even in setting of DNA damage and replication stress
Mismatch Repair (MMR) Deficiency	Recognise, excise and resynthesise mismatched or unmatched DNA base pairs or insertion-deletion loops.	MLH1, MSH2	MMR deficiency results in microsatellite instability, interfering with detection of cytotoxic DNA damage, allowing cancer cells to proliferate despite DNA damage.

DSBs; Double Strand DNA breaks, SSBs; Single Strand DNA breaks, PARPi; PARP inhibitor.