My note on paper: Targeting DNA Repair in Cancer: Beyond PARP Inhibitors
Paper: Targeting DNA Repair in Cancer: Beyond PARP Inhibitors
(doi: 10.1158/2159-8290.CD-16-0860)
There are two main concepts for the DNA repair targeting, as far as I have observed;
1. if using as the monotherapy, then we have to understand the genotype of tumor cells; which mutation signature that causes tumor cells remain "the particular DNA repair mechanism".
2. if using as adjuvant therapy, it means administrated as the combination with the current cytotoxic drugs, and observe the genotype of cancer cells --> which DNA repair pathway predominantly used by the tumor cells and target that.
Genetic signature of cancer cells is very important to use a tool to predict the therapeutic treatment choice.
---
Here comes to what I want to make a note from this paper.
DNA damage response;
1. how cell sense the damage
2. how cell sense the signal
3. how cell activate the cell cycle checkpoint
4. how cell trigger apoptosis
5. how cell orchestrates to initiate DNA repair
---
Clinical challenges;
1.therapeutic strategies targeting promising DDR targets
2. challenges in patient selection
3. development of rational drug combination
---
Table shows the major DNA repair pathway and the function in each pathway.
The figure exhibits the networks of protein involving in DNA damage response and DNA repair.
For the BRCA1/BRCA2(-/-) cells --> relied on PARP for DNA repair and PARP protein family play role in many cellular processes; differentiation, inflammation, gene transcription, mitosis, cell death... --> when applying the PARPi to the BRCA1/BRCA2(-/-) is very lethal to the cancer cells and finally kill the cancer cells.
This paper;
1. summarize the status of PARPi
2. look beyond to other proteins involving in cellular DDR
3. that DDR includes -- damage sensing, signaling pw that promote the cell-cycle checkpoint activation, and DNA damage repair.
This paper also wants to propose the enzymes that participate in DDR and they can be the new therapeutic targets.
In this paper, the author divided topic according to the process from DNA damage to DNA repair -- then the later part will be the applications to the clinical setting like, criteria to recruit patients, what kind of diagnostic test should be offered to the patients, what is the pitfalls that should be aware of if the DDR inhibitors are used. What is the remaining gap that should be investigated more.
Targeting the sensor;
-There are 17PARP family members;
PARP1 has more role in DNA repair, 2-3 have lesser extent
-PARP can recognize DNA breaks, DNA nicks, DSBs
-even though, PARPi is good for null BRCA1/2 or ATM --> there are the reports on the resistant toward using PARPi by which the cancer cells restore the HR function or by making the loss of 53BP1 can also rescue HR.
-the challenge is to optimize the efficacy of PARPi using and also investigate more on the PARPi resistant mechanism
Targeting the signaling protein;
DNA-damage signaling proteins;
for the DSB -- coordinated by PIKK (phosphatidylinositol 3-kinase-related kinases), DNA-PKcs (DNA-dependent serine-threonine protein kinase catalytic subunit), ATM, and ATR.
1. DNA-PKs
1.1. predominant DNA repair pw, esp, NHEJ
1.2. DNA-PK works together with Ku
DNA-PK inhibitor itself --> might give the modest anticancer activity since the break in cancer cells mostly can be repair through HR. However, giving the DNA-PK as the adjuvant with DNA-damaging agent --> might be the good benefits but need to concern on the therapeutic index
Each sensor recognized different DNA lesion and signal through different signaling pathways.
2.ATM
ATM is recruited after the MRN complex is formed. ATM is the kinase which will phosphate to g-H2Ax - then MDC1 (mediator of DNA damage checkpoint protein-1) binds to P-gH2Ax which is a megabase away from the lesion.
ATM can recognize chk1 (important for G1-S checkpoint activation), p53 and preventing it from degradation by MDM2
3.ATR
ATR is activated by RPA (replication protein A)-bound ssDNA; arise when there are the stalled replication or end resection at the early stage of HR. ATR recognize RPA-ssDNA and ATRIP. CHK1 is the substrate for ATR; CHK1 functions in G2-M and intra-S cell cycle.
ATR+CHK1 they have synthetic lethality affect; lost of function in either one is not lethal to the cells. It has a different role to control the intra-S checkpoint.
new kinase has been identified; MK2 and MAPKAP-K2 --> are the downstream substrate of ATM/ATR -->maintain G2-M and intra-S phase
4.CHK1
5.CHK2 -- Inhibition of CHK2 is still in question whether it will benefit to the clinical setting.
6.WEE1 -- protein kinase that play role in activation of G2-M checkpoint
Targeting the effector proteins;
There are some drugs that being on the clinical trials.
Fine-tuning DDR
This paragraph focuses on the regulating process of proteins involving in DDR to DNA repair.
Post-translational modification (PTM) process is the reversible process --> regulate the activity of DDR, using the inhibitor to disrupt in this step also have the same affect as targeting to the directed proteins.
There are inhibitors in preclinical and clinical phase that target on DNA repair through the targeting epigenetic modifier enzymes.
Patient selection
because of olaparib has a good effect on tumor cells with biallelic mutation/loss of BRCA1 or BRCA2 -- therefore, having the genetic testing (BRCAnalysis CDx) would give the benefit to the patients.
PARPi might be benefit to the other groups patient which have the HR defect and have the phenotype the same as BRCA1/2(-/-) --> BRCAness
Genomic defects resulting in HR deficiency are being utilized --> LOH, telomeric allelic imbalance and large scale state transitions like chromosomal break --> this could be benefit from PARPi.
Combination therapy
Toxicity (current conventional drugs; reduced dose?+DDR inhibitor) and specificity (patient group) are the major concerned
Beyond the targeted therapy is the hormonal effect that contributes to the DNA repair regulation.
There is the crosstalk between DNA-repair and endocrine signaling. Hormonal signaling act through the transcription activity which controls the function of protein in DNA repair.
(doi: 10.1158/2159-8290.CD-16-0860)
There are two main concepts for the DNA repair targeting, as far as I have observed;
1. if using as the monotherapy, then we have to understand the genotype of tumor cells; which mutation signature that causes tumor cells remain "the particular DNA repair mechanism".
2. if using as adjuvant therapy, it means administrated as the combination with the current cytotoxic drugs, and observe the genotype of cancer cells --> which DNA repair pathway predominantly used by the tumor cells and target that.
Genetic signature of cancer cells is very important to use a tool to predict the therapeutic treatment choice.
---
Here comes to what I want to make a note from this paper.
DNA damage response;
1. how cell sense the damage
2. how cell sense the signal
3. how cell activate the cell cycle checkpoint
4. how cell trigger apoptosis
5. how cell orchestrates to initiate DNA repair
---
Clinical challenges;
1.therapeutic strategies targeting promising DDR targets
2. challenges in patient selection
3. development of rational drug combination
---
DNA repair is important;
Defective in DNA repairs cause many diseases, e.g., neurodegeneration, infertility, immunodeficiencies, and cancer susceptibility.
Cancer cell relied on particular DNA repair pathway --> that is why making the cancer cells more sensitive to the DDR inhibitor rather than the normal which maintain full-DNA repair/DDR capacity.
defect in cell-cycle checkpoint activation+less DNA repair capability -->replication stress + accumulation of DNA damage
cancer cells often have dysfunctional redox homeostasis --> tremendously require mechanisms to repair oxidative DNA damage.
Table shows the major DNA repair pathway and the function in each pathway.
The figure exhibits the networks of protein involving in DNA damage response and DNA repair.
For the BRCA1/BRCA2(-/-) cells --> relied on PARP for DNA repair and PARP protein family play role in many cellular processes; differentiation, inflammation, gene transcription, mitosis, cell death... --> when applying the PARPi to the BRCA1/BRCA2(-/-) is very lethal to the cancer cells and finally kill the cancer cells.
This paper;
1. summarize the status of PARPi
2. look beyond to other proteins involving in cellular DDR
3. that DDR includes -- damage sensing, signaling pw that promote the cell-cycle checkpoint activation, and DNA damage repair.
This paper also wants to propose the enzymes that participate in DDR and they can be the new therapeutic targets.
In this paper, the author divided topic according to the process from DNA damage to DNA repair -- then the later part will be the applications to the clinical setting like, criteria to recruit patients, what kind of diagnostic test should be offered to the patients, what is the pitfalls that should be aware of if the DDR inhibitors are used. What is the remaining gap that should be investigated more.
Targeting the sensor;
-There are 17PARP family members;
PARP1 has more role in DNA repair, 2-3 have lesser extent
-PARP can recognize DNA breaks, DNA nicks, DSBs
-even though, PARPi is good for null BRCA1/2 or ATM --> there are the reports on the resistant toward using PARPi by which the cancer cells restore the HR function or by making the loss of 53BP1 can also rescue HR.
-the challenge is to optimize the efficacy of PARPi using and also investigate more on the PARPi resistant mechanism
DNA-damage signaling proteins;
for the DSB -- coordinated by PIKK (phosphatidylinositol 3-kinase-related kinases), DNA-PKcs (DNA-dependent serine-threonine protein kinase catalytic subunit), ATM, and ATR.
1. DNA-PKs
1.1. predominant DNA repair pw, esp, NHEJ
1.2. DNA-PK works together with Ku
DNA-PK inhibitor itself --> might give the modest anticancer activity since the break in cancer cells mostly can be repair through HR. However, giving the DNA-PK as the adjuvant with DNA-damaging agent --> might be the good benefits but need to concern on the therapeutic index
Each sensor recognized different DNA lesion and signal through different signaling pathways.
2.ATM
ATM is recruited after the MRN complex is formed. ATM is the kinase which will phosphate to g-H2Ax - then MDC1 (mediator of DNA damage checkpoint protein-1) binds to P-gH2Ax which is a megabase away from the lesion.
ATM can recognize chk1 (important for G1-S checkpoint activation), p53 and preventing it from degradation by MDM2
3.ATR
ATR is activated by RPA (replication protein A)-bound ssDNA; arise when there are the stalled replication or end resection at the early stage of HR. ATR recognize RPA-ssDNA and ATRIP. CHK1 is the substrate for ATR; CHK1 functions in G2-M and intra-S cell cycle.
ATR+CHK1 they have synthetic lethality affect; lost of function in either one is not lethal to the cells. It has a different role to control the intra-S checkpoint.
new kinase has been identified; MK2 and MAPKAP-K2 --> are the downstream substrate of ATM/ATR -->maintain G2-M and intra-S phase
4.CHK1
5.CHK2 -- Inhibition of CHK2 is still in question whether it will benefit to the clinical setting.
6.WEE1 -- protein kinase that play role in activation of G2-M checkpoint
Targeting the effector proteins;
There are some drugs that being on the clinical trials.
Fine-tuning DDR
This paragraph focuses on the regulating process of proteins involving in DDR to DNA repair.
Post-translational modification (PTM) process is the reversible process --> regulate the activity of DDR, using the inhibitor to disrupt in this step also have the same affect as targeting to the directed proteins.
There are inhibitors in preclinical and clinical phase that target on DNA repair through the targeting epigenetic modifier enzymes.
Patient selection
because of olaparib has a good effect on tumor cells with biallelic mutation/loss of BRCA1 or BRCA2 -- therefore, having the genetic testing (BRCAnalysis CDx) would give the benefit to the patients.
PARPi might be benefit to the other groups patient which have the HR defect and have the phenotype the same as BRCA1/2(-/-) --> BRCAness
Genomic defects resulting in HR deficiency are being utilized --> LOH, telomeric allelic imbalance and large scale state transitions like chromosomal break --> this could be benefit from PARPi.
Combination therapy
Toxicity (current conventional drugs; reduced dose?+DDR inhibitor) and specificity (patient group) are the major concerned
Beyond the targeted therapy is the hormonal effect that contributes to the DNA repair regulation.
There is the crosstalk between DNA-repair and endocrine signaling. Hormonal signaling act through the transcription activity which controls the function of protein in DNA repair.
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