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Hitting BRCA1/2 Mutant Cells in their Achilles Heel
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- This deletion causes a frameshift, which leads to a stop codon in its place and
thus the truncation of the protein
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Most people have two normal BRCA2 genes, but carriers of mutations have one
normal and one fault gene
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- Therefore, cancers develop from cell that lost the final normal BRCA2 copy
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What do the normal BRCA1 and 2 proteins do in the cell?
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- Differential mutational processes often generate different combinations of
mutation types, and are termed ‘signatures’
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o This means that the BRCA2 genome is unstable, and is possibly due to
faulty DNA repair mechanisms
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o An inherited mutant copy increases the risk of developing serial
mutations that are needed to develop cancer
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- This complexity increases the risk of treatment failure and tumour
aggressiveness
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Common DNA damaging agents, examples of DNA lesions induced by these
agents, and the most relevant DNA repair mechanism responsible for the
removal of the lesions
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Loss of the BRCA1/2 protein in a risk tissue cell inhibits homologous recombination
(HR) repair
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- Whereas, the alternative pathway would be used very little
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- The functioning BRCA1/2 proteins would be used to repair the DNA but to a
much smaller capacity
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This means that when HR fails, other DNA processes (NHEJ) take over thus driving a
mutator phenotype:
- In the absence of BRCA1 or BRCA2 function, chromatid breaks accumulate,
resulting in aberrant chromatid exchanges or other processes involving
illegitimate end-joining
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If an exchange is made with a chromatid fragment without a centromere,
processing and cell division can produce a viable cell with a translocation
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All of the hallmarks of BRCA-deficient cancers can be explained by the production
of chromatid breaks and illegitimate end-joining
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The mutator phenotypes that define this complex genome variability may be
“actionable” targets but only if the trunk of the tree is targeted, thus minimising off
targeting and side effects
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Poly (ADP-ribose) polymerase inhibitors (PARPi) is activated by DNA breaks and
cleaves nicotinamide adenine dinucleotide (NAD+) generating nicotinamide and ADPribose
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- These loosen chromatin and recruit scaffold proteins and other histone
remodelling enzymes, which in turn recruit DNA polymerase b and ligase III to fill
in and re-seal the gap
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Role 4: Synthetic sickness
o In combination with drugs to be active in tumours which have HR defects
(i
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platinum salts)
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In the presence of functional BRCA1 and BRCA2, the proximity of an undamaged
sister chromatid template to the DSB allows the invasion of the sister chromatid
by a RAD51-coated single-stranded DNA filament, and initiation of sister
chromatic recombination repair
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In the absence of functional BRCA1/2, sister chromatid recombination and the
formation of RAD51 foci are severely impaired
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o Some remain unrepaired as chromatid breaks but many are repaired by
error-prone RAD51-independent mechanisms, such as NHEJ and SSA
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- Furthermore, targeting BRCA leads to tumour selective killing
o Normal cells have two normal copies of the gene and thus carry out HR
repair after DNA damage
o However, the cells of a carrier means that in response to DNA damage
and PARPi administration, the tumour cells will be forced to undergo
senescence as they cannot undergo HR or BER (base excision repair –
carried out by PAPR)
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Olaparib:
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2010) found that in patients who had
received a median of 3 previous chemotherapy regiments and the maximum
tolerated dose of olparib, there was a 41% overall response rate
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- BRCA2-mutated cancer cells selected in the presence of cisplatin acquired
secondary genetic changes on the mutated BRCA2 allele, which cancelled the
frameshift caused by the inherited mutation
- Thus restoring expression of functional nearly-full-length BRCA2 proteins
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(2012) were able to
demonstrate that olaparib can function as maintenance treatment and significantly
improved the progression free survival among patients with platinum sensitive,
relapsed, high grade serous ovarian cancer
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Lynparza is a drug, approved by the FDA for patients with specific abnormalities in
the BRCA gene – with a long-term survival rate in patients with advanced ovarian
cancer of 10-30%
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This drug is also investigating the use of this drug in BRCA1/2 carriers with breast
cancer, and early reports have shown that it provided a statistically-significant
improvement in progression-free survival compared to chemotherapy
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Current trials are investigating whether PARPi can be used to cure women of cancer,
particularly women for high risk metastatic, genetic forms of the disease
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There is currently no tailored therapy for human basal-like mammary carcinomas,
however, BRCA1 dysfunction is frequently present in these malignancies,
compromising homology-directed DNA repair
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This defect may function as the tumour’s Achilles heel and make the tumour
hypersensitive to DNA breaks
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Research has found that BRCA1 mutant basal-like breast cancer has specific
chemosensitivities, when treated with the PARPi, olaparib
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- This demonstrates the importance of identifying the genetic forms of the cancer
first in order to provide maximum therapeutic benefit to the patients
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This is further corroborated by a study by Davies et al
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7% sensitivity to
PARPi
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- Therefore, trials specific to populations of women with uncommon but
important genetic forms of breast cancer are possible and should continue to be
conducted