PARP inhibitors, Progression, Performance, Adverse Events and Current Perspective on Resistance Development.
Ideally, effective cancer therapies utilize unique vulnerabilities of tumor cells without affecting the normal cell mass. Today, we will discuss how PARP inhibitors (PARPi) target unique DNA repair deficiency of tumor cells.
By Ajay V. Patil
DNA repair and Poly-ADP Ribose Polymerase (PARP)
Single strand DNA break is a common DNA lesion. These single strand DNA nicks are either generated by exogenous mutagenic stress or created by the DNA repair machinery during the repair process of various DNA lesions. PARP functions at the exact site of single strand DNA break. There are about 17 members of the PARP family that are encoded by different genes and share homology in a conserved catalytic domain. PARP1 is considered as the main catalytic protein which binds to the single strand nick, undergoes conformational changes and initiates the repair process by recruiting downstream repair proteins like XRCC1, ligase and polymerase .
Synthetic lethality – Rationale of PARPi therapy in BRCA positive and negative cohorts
Inhibition of PARP leads to conversion of unrepaired single strand breaks into double strand breaks. BRCA plays major role in the repair of these double strand mutations through homologous recombination (HR) pathway. In many tumor cells (BRCA negative), loss of major HR genes (like BRCA1 and/or 2) leads to HR deficiency and consequent sensitivity to PARP inhibitor treatment . Thus clinically there are two patient populations which can be targeted using PARP inhibitors. In the first cohort of BRCA negative patients, tumor cells rely on PARP for DNA repair and inhibiting PARP activity leads to tumor cell death. In the second cohort of BRCA positive patients undergoing chemotherapy, drug induces single strand nicks in tumor cell DNA. Further these cells can be differentially targeted by PARP inhibitors .
AZD2281 (Olaparib) development and approval
First in human phase I study by AstraZeneca used AZD2281 to show how much dose patients could tolerate. They showed that drug reduced the size of abdominal tumors dramatically. The trial had 11 BRCA carrier ovarian cancer patients in the initial phase . About 50% patients with BRCA ovarian cancer responded to the treatment. Among them, patients with platinum sensitive disease showed dramatic response (about 80%). Most of the patients had no or mild toxicities including nausea, vomiting, loss of appetite and fatigue [4,5,6]. Subsequently drug progressed through clinical trials with minor hiccups and was approved for monotherapy in 2014.
Mechanism of resistance development
Several resistance mechanisms have been studied using both in vitro and in vivo models. Restoration of HR pathway, PARP1 drug binding site mutation, loss of NHEJ pathway and oncogene overexpression are among few of those mechanisms. Restoration of HR pathway is a well studied phenomenon. Secondary mutations in BRCA1 and RAD51C/D which can restore the HR function are widely reported with supporting in vitro studies [7, 8]. At least 30 other HR related genes like Chk 1,2 and ATM are speculated to be involved in the resistance development of drug resistance . While the intertwined resistance pathways are gradually being unraveled, PARP inhibitors can now be adapted to a broader indication range. Additionally some trials evaluating the effect of PARP inhibitors in combination with checkpoint immunotherapies, HSP90 inhibitors and anti-angiogenic agents will provide evidences which can dramatically change the cancer therapy in the future .
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- Sunanda S. et al., Cancer Sci., 2018
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- Dr. Ursula Matilonis and Dr. Thomas Herzog presentations at The Clinical Potential of Novel Poly ADP-Ribose Polymerase Inhibitors for Improved Management of Epithelial Ovarian Cancer, a satellite symposium – adjunct with ASCO 2015
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