DNA is damaged thousands of times during each cell cycle, and that damage must be repaired, including in cancer cells. Otherwise the cells may die due to this damage. BRCA1, BRCA2 and PALB2 are proteins that are important for the repair of double-strand DNA breaks by the error-free homologous recombinational repair, or HRR, pathway. When the gene for one of these proteins is mutated, the change can lead to errors in DNA repair that can eventually cause breast cancer. When subjected to enough damage at one time, the altered gene can cause the death of the cells. PARP1 is a protein that is important for repairing single-strand breaks. If such nicks persist unrepaired until DNA is replicated, then the replication itself can cause double strand breaks to form. Drugs that inhibit PARP1 cause multiple double strand breaks to form in this way, and in tumours with BRCA1, BRCA2 or PALB2 mutations, these double strand breaks cannot be efficiently repaired, leading to the death of the cells. Normal cells that don't replicate their DNA as often as cancer cells, and that lack any mutated BRCA1 or BRCA2 still have homologous repair operating, which allows them to survive the inhibition of PARP. PARP inhibitors lead to trapping of PARP proteins on DNA in addition to blocking their catalytic action. This interferes with replication, causing cell death preferentially in cancer cells, which grow faster than non-cancerous cells. Some cancer cells that lack the tumor suppressor PTEN may be sensitive to PARP inhibitors because of downregulation of Rad51, a critical homologous recombination component, although other data suggest PTEN may not regulate Rad51. Hence PARP inhibitors may be effective against many PTEN-defective tumours. Cancer cells that are low in oxygen are sensitive to PARP inhibitors.
Approved for marketing
Olaparib: In December, 2014, the EMA and US FDA approved olaparib as monotherapy for patients with germline BRCA mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.
Rucaparib: On December 19, 2016 the US FDA granted accelerated approval for previously treated BRCA-mutant ovarian cancer. In April 2018 it was granted FDA approval.
Talazoparib after trials for advanced hematological malignancies and for advanced or recurrent solid tumors. it started in 2013 a phase III for metastatic germline BRCA mutated breast cancer.
Iniparib was determined in 2012 not to be a true PARP inhibitor and failed trial for triple negative breast cancer. In 2013 Sanofi disclosed that iniparib failed to help squamous cell lung cancer patients in a phase III trial, prompting the company to end research into the once-promising compound.
The main function of radiotherapy is to produce DNA strand breaks, causing severe DNA damage and leading to cell death. Radiotherapy has the potential to kill 100% of any targeted cells, but the dose required to do so would cause unacceptable side effects to healthy tissue. Radiotherapy therefore can only be given up to a certain level of radiation exposure. Combining radiation therapy with PARP inhibitors offers promise, since the inhibitors would lead to formation of double strand breaks from the single-strand breaks generated by the radiotherapy in tumor tissue with BRCA1/BRCA2 mutations. This combination could therefore lead to either more powerful therapy with the same radiation dose or similarly powerful therapy with a lower radiation dose.
