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  In this article
 »  Abstract
 » Introduction
 »  Poly (ADP-ribose...
 » PARP Inhibitors
 »  Indications of P...
 »  Patient Selectio...
 »  Increase in Resi...
 »  Overcoming Resis...
 »  Clinical Use of ...
 » Conclusion
 » Acknowledgments
 »  References
 »  Article Figures
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  Table of Contents  
Year : 2022  |  Volume : 59  |  Issue : 5  |  Page : 119-129

A review on mechanisms of resistance to PARP inhibitors

1 Medical Oncology, Vedanta Institute of Medical Sciences, Ahmedabad, Gujarat, India
2 Medical Oncology, National Cancer Institute, Nagpur, Maharashtra, India
3 Medical Oncology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
4 Medical Oncology, Mumbai Oncocare Centre, Mumbai, Maharashtra, India
5 Medical Affairs, AstraZeneca Pharma India Ltd, Bangalore, Karnataka, India

Date of Submission12-Jan-2021
Date of Decision15-Feb-2021
Date of Acceptance14-Oct-2021
Date of Web Publication24-Mar-2022

Correspondence Address:
Chirag Desai
Medical Oncology, Vedanta Institute of Medical Sciences, Ahmedabad, Gujarat
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_53_21

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 » Abstract 

Standard therapy for advanced ovarian cancer (OC) consists of radical debulking cytoreductive surgery followed by adjuvant chemotherapy. An important risk factor for OC is genetic predisposition, with BRCA1 or BRCA2 mutations accounting for the majority of hereditary OC. Mutation in BRCA ultimately causes accumulation of genetic alterations because of the failure of cells to arrest and repair DNA damage or to undergo apoptosis, resulting in tumorigenesis. Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as a promising approach for managing BRCA-associated cancers, especially high-grade OC and breast cancers. They lead to synthetic lethality in BRCA-mutated cells by stalling the replication forks in homologous recombination-deficient (HR) cells. Four PARP inhibitors (olaparib, niraparib, rucaparib, and talazoparib) are currently approved by the Food and Drug Administration for OC, breast, and pancreatic cancer indications and are being evaluated for other BRCA-associated cancers. Despite their clinical efficacy, cancer cells generally develop resistance to them through several mechanisms. Understanding these mechanisms is crucial for developing strategies to counter resistance and identify the basic mechanisms of DNA damage response. This review focuses on the mechanism of action of PARP inhibitors, understanding various causes of resistance, and building strategies to overcome PARP inhibitor resistance.

Keywords: BRCA mutations, DNA repair, niraparib, olaparib, PARP inhibitors, resistance, rucaparib

How to cite this article:
Desai C, Pathak A, Limaye S, Maniar V, Joshi A. A review on mechanisms of resistance to PARP inhibitors. Indian J Cancer 2022;59, Suppl S1:119-29

How to cite this URL:
Desai C, Pathak A, Limaye S, Maniar V, Joshi A. A review on mechanisms of resistance to PARP inhibitors. Indian J Cancer [serial online] 2022 [cited 2022 May 22];59, Suppl S1:119-29. Available from:

 » Introduction Top

Inhibition of cellular repair in cancer cells represents an attractive strategy for potentiating the cytotoxic effects of chemotherapy. Of the known DNA repair inhibitors, poly (ADP-ribose) polymerase (PARP) inhibitors provide a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways in a variety of cancer types.[1] PARP inhibitors are representative of advances in precision medicine, with breakthroughs achieved in the management of advanced and recurrent ovarian cancer (OC).[2] Moreover, PARP inhibitors are effective anticancer drugs that produce a good initial clinical response, especially in homologous recombination (HR) DNA repair-deficient cancers,[3] where they were first observed to be effective. Notably, up to 50% of all high-grade serous ovarian cancers (HGSOC) have deficiencies in the HR DNA repair pathway, including breast cancer type 1/2 susceptibility protein (BRCA1/2) mutations. Although PARP inhibitors are being used predominantly to manage recurrent OCs with defective HR repair pathways, significant clinical benefits are also demonstrated in patients without HR deficiencies.[2]

Olaparib, rucaparib, niraparib, and talazoparib are the four United States Food and Drug Administration (US FDA)-approved PARP inhibitors, of which olaparib is the only PARP inhibitor currently approved in India. Treatment with PARP inhibitors exploits the concept of synthetic lethality, a phenomenon in which two genetic mutations are harmless when they occur separately but can result in cell death when they occur in combination.[4],[5] The greatest advantage of exploiting synthetic lethality is that the tumor tissue with mutations is selectively targeted, resulting in decreased toxicity to normal cells.[6] However, similar to other targeted therapies approved for cancer, the clinical benefit of PARP inhibitors in patients with BRCA1/2-mutated tumors is eventually countered by the emergence of drug resistance. Thus, understanding the underlying mechanisms is not only critical for developing strategies to counter PARP inhibitor resistance but also to gain novel insights into the basic mechanisms of DNA damage response. PARP inhibitors that are currently under development or approved for therapy hold the potential to deliver considerable clinical benefit to patients by a targeted mechanism. This review aims to decode the mechanism of action of PARP inhibitors, understand the mechanisms of resistance, and investigate different strategies to overcome this challenge of resistance.

 » Poly (ADP-ribose) Polymerase Top

The living cell, including its proteins and DNA, encounters various assaults on its native structure and sequence throughout its life span. Human cells have at least five primary pathways of DNA repair that serve as a probe and identify defects to protect the genome. The major DNA repair pathways are direct repair, mismatch repair, base excision repair (BER), nucleotide excision repair, and double-strand break (DSB) repair. DSB repair includes both nonhomologous end-joining (NHEJ) and homologous recombinational repair. Dysfunction, reduction, or absence of proteins committed to these pathways may lead to disastrous cellular consequences, causing mutagenesis and toxicity.[6],[7]

BRCA1 and BRCA2 proteins play the important role of a transcriptional regulator through activation of specific DNA repair processes in response to cell damage. Both the BRCA1 and BRCA2 proteins are often found in stable interaction, suggesting cofunction of these proteins in pathways of tumor suppression.[6]

The PARPs are the family of enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins (poly ADP-ribosylation). Poly (ADP)-ribosylation is an immediate DNA damage-dependent post-translational modification of histones and other nuclear proteins that contribute to the survival of the injured proliferating cells. There are at least 18 members of the PARP family that are encoded by different genes and share homology in a conserved catalytic domain.[8],[9] Two isoforms of PARP, namely PARP1 and PARP2, are best known for their involvement in the DNA repair process. They also play an important role in several cellular processes, including cell proliferation and death.[9] PARP1 and PARP2, when activated by DNA damage, facilitate DNA repair in pathways involving single-strand breaks (SSBs) and BER [Figure 1].
Figure 1: Role of PARP in DNA repair mechanism[9]. BER = base excision repair; NAD+ = nicotinamide adenine dinucleotide; PARP = poly (ADP-ribose) polymerase; SSB = single-strand break; XRCC1 = Xray repair cross-complementing protein 1. PARP-1 is activated by DNA breaks and cleaves NAD + generating nicotinamide and ADP-ribose. Successive addition of ADP-ribose units forms long and branched chains of poly (ADP-ribose) (PAR), covalently attached to acceptor proteins (PARP-1, histone, and other DNA repair proteins), resulting in polymers adjacent to the DNA breaks. These highly negatively charged polymers form a scaffold and recruit other proteins that are critical in BER/SSBR, for example, XRCC1

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PARP1 consists of three major domains: an NH2-terminal DNA damage-sensing and binding domain containing three zinc fingers, an automodification domain, and a C-terminal catalytic domain. Zinc finger-2 has the strongest affinity for DNA breaks while zinc finger-1 is responsible for DNA-dependent PARP-1 activation, in which zinc finger 3 also participates. Moreover, other proteins involved in chromatin remodeling, chromosomal organization, DNA repair, and transcription and cell cycle regulation may also bind to the polymers noncovalently. PARP-2 was discovered serendipitously when it was noted that cells from PARP-1 knockout mice generate ADP-ribose polymers from nicotinamide adenine dinucleotide (NAD)+ in response to DNA damage.[1] The catalytic domain of PARP-2 has a strong similarity to PARP-1 and targets DNA gaps and not nicks.[10] Since the discovery of PARP-1 and PARP-2, a family of 18 proteins with structural similarity to the PARP-1 catalytic domain have been identified, but only PARP-3, vault PARP, and tankyrases 1 and 2 have proven ADP-ribose polymerizing activity.[1]

 » PARP Inhibitors Top

Poly (ADP)-ribosylation is involved in the regulation of cellular processes such as DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions, and genomic stability. Among the 18 PARP analogs identified so far, PARP-1 and PARP-2 are the only proteins that get stimulated by DNA strand breaks and implicated in the repair of DNA injury. Therefore, these molecules have been identified as potential targets for the development of pharmacological strategies to increase the antitumor efficacy of chemotherapeutic agents, which induce DNA damage.[11] Along with PARP, BRCA1 and BRCA2 have a dual role to protect the human genome, which includes HR repair and protection of stalled replication forks. With HR repair, a cell can efficiently perform the error-free repair of a DSB in the S phase. BRCA1 functions to promote the 5′ to 3′ resection of the DSB, leaving behind a 3′ overhang. Thereafter, BRCA2 loads the overhang with RAD51, creating a nucleofilament suitable for invasion of a wild-type sister chromatid template through the process of “D” loop formation. Cells deficient in HR repair must rely on an alternative mechanism of DSB repair, such as classicalNHEJ, alternative end-joining, or single-strand annealing. Replication fork protection is largely governed by the upregulation of the ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) and its major downstream effector checkpoint kinase1 pathway, leading to the loading of BRCA1 and BRCA2 at the stalled fork.[12]

Several types of human tumors, including ovarian, breast, prostate, and pancreatic cancers, have underlying defects in HR repair. The HR repair defects in HGSOC (high-grade serous ovarian cancer) result from either germline or somatic mutation of one or more BRCA genes. Ten to twenty percent of breast tumors (mainly, triple-negative breast tumors), metastatic prostate cancers, or pancreatic cancers harbor biallelic mutations in HR genes, making them candidates for PARP inhibitor therapy as well.[12] Suppression of PARP activity increases cell susceptibility to DNA-damaging agents and inhibits strand break rejoining. In addition to other pathways, repair pathways like HR can correct PARP inhibition-induced DNA lesions. Therefore, PARP inhibition is not lethal in isolation. However, in patients with BRCA1 or BRCA2 mutations, the HR pathway is defective, and hence, DNA lesions caused by PARP inhibition cannot be repaired and evolve into DSB with tumor cytotoxicity, thus exploiting the principle of synthetic lethality.[13] Thus, PARP inhibitors are being proposed as the ultimate tumor-specific therapy for tumors with BRCA mutations, targeting only the cancer cells without affecting the normal cells.

Mechanism of action of PARP inhibitors

PARP inhibitors structurally mimic nicotinamide and act mainly through two pathways: catalytic inhibition of PARP1 (i.e. preventing PARylation) and locking or “trapping” PARP1 on damaged DNA [Figure 2]. Exact mechanisms of PARP1 trapping are still unclear; however, two mechanisms have been proposed: (i) PARP inhibitors either prevent the release of PARP1 from DNA by inhibiting autoPARylation, or (ii) PARP inhibitors' binding to the catalytic site causes allosteric changes in the PARP1 structure, enhancing the DNA avidity. In both, trapped PARP1 stalls the progress of replication forks. In normal cells, these stalled replication forks would be repaired by HR. In tumor cells that lack one of the key HR proteins, such as BRCA1, BRCA2, PALB2, or RAD51, an alternative DNA repair mechanism attempts to repair DNA lesions caused by PARP inhibition, primarily through NHEJ or Alt-NHEJ. Instead of restoring the damaged DNA sequence to its native form, the use of error-prone DNA repair pathways leads to fragmentation of the genome that ultimately kills the cell.[13],[14]
Figure 2: Mechanism of action of PARP inhibitors[14]. BER = base excision repair; DSBs = double-strand breaks; HRR = homologous recombination repair; PARP = poly (ADP-ribose) polymerase; PARPi = poly (ADP-ribose) polymerase inhibitors; SSBs = single strain breaks

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 » Indications of PARP Inhibitors Top

PARP inhibitors are indicated for the maintenance treatment of OC,  Fallopian tube More Details, primary peritoneal, and breast cancer.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18] [Table 1] summarizes the indications for approved PARP inhibitors.
Table 1: Approved indications for PARP inhibitors[15],[16],[17],[18]

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Olaparib and talazoparib were approved for metastatic breast cancer based on OlympiAD and EMBRACA studies.[19],[20] The efficacy and safety of PARP inhibitors have been investigated for prostate and pancreatic cancers. The PROFOUND study, which evaluated olaparib versus enzalutamide or abiraterone, showed benefit in overall survival in subjects with metastatic castration-resistant prostate cancer, 19.1 months in the olaparib arm vs. 14.7 months in the new hormonal agents (NHAs) arm in the cohort A (HR 0.69, P = 0.0175).[17] Another phase III study, POLO (NCT02184195), which evaluated the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and pancreatic cancer, reported significant progression-free survival (PFS) benefit.[21] In the PAOLA trial, olaparib in combination with bevacizumab also showed significant improvement in PFS in newly diagnosed, advanced, high-grade OC (22.1 vs. 16.6 months; P < 0.001), irrespective of BRCA status. The PFS in the HRD positive subgroup was 37.2 months vs. 17.7 in the placebo arm (hazard ratio for disease progression or death: 0.33; 95% CI: 0.25–0.45).[22] Niraparib showed positive results in newly diagnosed advanced OC in a randomized clinical study. The corresponding progression-free survival in the overall population was 13.8 months and 8.2 months, respectively (hazard ratio: 0.62; 95% CI: 0.50–0.76; P < 0.001).[23] In the phase III VELIA study, veliparib in combination with carboplatin and paclitaxel followed by veliparib monotherapy as maintenance treatment showed a PFS (measured from the point of randomization into the trial, i.e. the time that the patients were randomized to receive carboplatin and paclitaxel with or without veliparib) of 34.7 months compared with chemotherapy alone (22.0 months) in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma.[24] Emerging studies suggest that PARP inhibition can also target HRcompetent cancers, such as non-small-cell lung cancer (NSCLC).[25]

 » Patient Selection for PARP Inhibitors: Role of Predictive Biomarkers Top

An accurate predictive biomarker can optimize clinical responsiveness to PARP inhibitor therapy. However, the identification of a reliable biomarker for response to PARP inhibition is exceptionally challenging because of inconsistencies from various investigative approaches.[14] HR deficiency and PARP activity are well-known biomarkers of PARP inhibitors [Figure 3].
Figure 3: PARP1 inhibitor biomarkers[24]. ATM = ataxia telangiectasia mutated; BRCA = breast cancer gene; HR = homologous recombination; FANCF = Fanconi anemia, complementation group F; PAR = poly (adenosine diphosphate-ribose); PARP1i = poly (adenosine diphosphate-ribose) polymerase 1 inhibitors; PTEN = phosphatase and tensin homolog

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Homologous recombination deficiency

Homologous recombination is a prime pathway for the repair of DNA DSBs in human cells. BRCA1/2, the key proteins at different stages of HR, are frequently mutated in breast and OC. Apart from the BRCA1/2, other HR proteins, such as phosphatase and tensin homolog (PTEN), ataxiatelangiectasia mutated (ATM), MRE11, and Fanconi anemia complementation group F (FANCF), have also been identified as related to cancer.[26],[27] BRCAness profile contains around 60 genes that help distinguish BRCA-like from non-BRCA-like tumor with 94% accuracy.[28] PARP inhibitor decreases SSB repair but increases the DSBs that require HRmediated repair. In this way, proteins involved in the HR pathway are considered as biomarkers of PARP inhibitors.[29]

PARP activity

PARP activity is another biomarker of PARP inhibitor action. Cytoplasmic PARP expression can be detected in all subtypes of early breast cancers and is correlated with a biological tumor pattern. It is suggested that cytoplasmic PARP expression may be a biomarker for the benefit of neoadjuvant chemotherapy.[30] However, PARP activity is not regulated by the level of PARP but is determined by post-translational modification or endogenous activation.[31] Various parameters such as DNA breaks or BRCA mutation can also increase PARP activity. The presence of poly (ADP-ribose) polymers may be useful in identifying cancer that can respond to PARP inhibitor therapy.[24],[32]

Mechanism of resistance to PARP inhibitors

As PARP inhibitor use becomes more prevalent, resistance is likely to develop and become clinically significant. Emerging drug resistance has been observed in patients with advanced BRCA1/2-mutated cancer. PARP inhibitor-treated cells acquire resistance either directly or indirectly. The common mechanisms of resistance to PARP inhibitors are listed in [Box 1].[3]

Restoration of HR pathway/BRCA1-2

The most common mechanism of resistance to the PARP inhibitors is related to reactivation of HR, which occurs either through the restoration of BRCA1/2 activity or by rewiring of the DNA damage response network.[7],[33]

i. Reactivation of the BRCA1/2 Activity

The BRCA1/2 proteins work in two distinct cellular processes, namely the execution of HR repair and the protection of the stalled replication fork. To become resistant, tumor cells can find a way to restore HR repair, perhaps by generating a somatic reversion in mutated BRCA1/2 proteins.[12],[34],[35] The prevalence of restoration of BRCA1/2 activity varies between studies. BRCA1/2 reactivation was reported in 21% and 40% of ovarian and breast cancer patients, respectively.[36] In another study, in BRCA-mutated cancers treated with platinumbased therapy, 46% of platinum-resistant BRCA-mutated HGSOC exhibited tumorspecific secondary mutations that restored the open reading frame (ORF) of either BRCA1/2. Restoration of BRCA1/2 activity occurs either by genetic events that cancel the frameshift caused by the original mutation and restore the ORF, or by genetic restoration of the inherited mutation; both restore a full-length wild-type protein. HR repair can also be restored by reversal of BRCA1 promoter methylation.[12] In a study, approximately 46% of platinumresistant OC recurrences had secondary somatic mutations restoring BRCA1/2 in women with germline BRCA1/2 mutations.[33] Numerous case reports and cohort studies in subjects with cancer confirmed the reactivation of somatic BRCA function in resistant tumors, including breast,[37] ovarian,[38] and pancreatic[39] cancers.

ii. Inactivation of the 53BP1 Pathway in BRCA1-deficient Tumors

Various mechanisms of resistance involving the reacquisition of DNA end resection capacities have also been identified. Several proteins are involved in a pathway that suppresses end resection and thereby inhibits HR repair. These proteins include 53-binding protein-1 (53BP1), REV7, Pax transactivation domain-interacting protein (PTIP), and replication timing regulatory factor 1 (RIF1). Discovery of this mechanism came from the observation that the requirement of BRCA1 for HR can be alleviated by concomitant loss of 53BP1. Hence, inactivation of these proteins was shown to confer PARP inhibitor resistance.[14]

Recently, genetic screens for PARP inhibitor resistance factors and proteomic analyses of the DNA damage response network yielded a novel four-subunit protein complex named Shieldin, which is composed of SHLD1, SHLD2, SHLD3, and REV7 proteins.[32],[40] Shieldin factors are recruited to DSB sites in a 53BP1- and RIF1-dependent manner, and their disruption results in restoration of HR and PARP inhibitor resistance in BRCA1-deficient cells.[32]

Several other factors that affect end resection and modulate PARP inhibitor response in BRCA1-deficient cells have also been identified. Loss of members of the CTC1-STN1-TEN1 (CST) complex restores DNA end processing in the absence of BRCA1 and limits PARP inhibitormediated toxicity.[41]

Another resection antagonist implicated in PARP inhibitor resistance is DNA helicase B (HELB), which acts independently of 53BP1 and is not involved in the choice of the DSB pathway. Instead, HELB reinforces a feedback inhibition mechanism that reduces ongoing end processing and prevents long-range resection. Loss of HELB leads to restoration of HR and PARP inhibitor resistance in BRCA1-deficient cells; however, these effects are less pronounced as compared to 53BP1 depletion.[42]

Other mechanisms of resistance resulting in restoration of HR pathway include ORF of BRCA-2, PALB2, or RAD51C/D in tumors with frameshift or nonsense mutations, which results in demethylation in the promoter regions of DNA. This is associated with mRNA re-expression and PARP inhibitor resistance.[36],[43],[44],[45]

Upregulation of drug efflux

Resistance to anticancer drugs because of an increased drug efflux represents a well-known phenomenon. Upregulation of drug transporters prevents sufficient accumulation of various anticancer compounds in the cells, which ultimately results in reduced therapeutic action or drug resistance.[46] An earlier study analyzing PARP inhibitor refractory mouse mammary tumors revealed upregulation of the P-glycoprotein drug efflux transporter. Coadministration of PARP inhibitor, olaparib, and the specific P-glycoprotein inhibitor tariquidar restored PARP inhibitor sensitivity in tumors.[47]

Downregulation of PARP1 expression

As PARP inhibitors act by blocking the enzymatic action of PARP enzymes, another possible mechanism of PARP inhibitor resistance can be decreased expression of PARP enzymes. This mechanism of resistance may be particularly relevant to the PARP-trapping mechanism of action of PARP inhibitors.[13] Intramolecular interactions can influence PARP1 binding with DNA and its activation, and thereby alter the trapping of PARP1 by PARP inhibitors, which results in resistance.[32]

 » Increase in Resistant Cells Top

An increase in resistant cells mediated by cancer stem cell-related mechanisms has been reported in preclinical studies on triple-negative breast cancer (TNBC). Increased levels of RAD51 were shown to contribute to PARP inhibitor resistance. Treatment with PARP inhibitors might lead to an increase in cancer stem cells because of an elevated homologous recombination repair mechanism mediated by RAD51 expression. Increased RAD51 expression has been observed in cancer stem cells of BRCA-mutant TNBC. In TNBC cell lines, downregulation of the early mitotic inhibitor 1 (EMI1), which assembles the ubiquitin ligase complex to degrade RAD51, induces PARP inhibitor resistance. Thus, increased efficiency of the DNA repair mechanism might contribute to the PARP inhibitor resistance.[48],[49]

Another mechanism of increase in resistance cells involves zeste homolog 2 (EZH2), an enzyme that catalyzes H3 lysine trimethylation. PARP1 also induces PARylation of EZH2 and contributes to PARP inhibitor sensitivity in breast cancer cells. Inhibition of PARP by PARP inhibitor attenuates alkylating DNA damage-induced EZH2 downregulation, thus promoting EZH2-mediated gene silencing and cancer stem cell property compared with PARP inhibitoruntreated cells.[50]

Increased PARP Activity

Theoretically, increased PARP activity should lead to increased sensitivity to PARP inhibitors. However, in the case of targeted therapies such as PARP inhibitors, overexpression of the target could increase the drug concentration required to inhibit it. Changes in PARP1 expression levels in cancer cells cause resistance to PARP inhibitors, which is related to poor prognosis in breast cancer patients.[51]

In preclinical studies, c-MET proto-oncogene is also related to PARP inhibitor resistance in TNBC cells and was associated with poor prognosis, while knockdown of c-MET led to higher sensitivity to PARP inhibitors. c-MET phosphorylates PARP1 at Tyr907 site and Tyr907 phosphorylated PARP1 shows higher enzyme activity and lower binding activity to PARP inhibitors compared to non-phosphorylated PARP, which promotes tumor cells to develop PARP inhibitor resistance.[52],[53]

Restoration of stalled replication fork protection

Apart from the mechanisms of resistance intrinsic to the DNA damage response, BRCA1/2-deficient tumor cells can protect against genome instability by maintaining replication fork integrity under conditions of replicative stress. BRCA1-deficient cells were shown to become resistant to PARP inhibitors by reducing the recruitment of the nuclease, MRE11, to the stalled fork, thereby resulting in fork protection.[54],[55] Extensive resection of DNA termini at stalled replication fork results in replication fork collapse and DSB formation. Therefore, loss of fork protection may contribute to the hypersensitivity of BRCA-deficient cells to chemotherapy or PARP inhibitors, which enhance replication stress. In line with this, several mechanisms that restore replication fork protection can cause resistance to the PARP inhibitors.[56] The BRCA1-deficient cells reduce the expression of the PTIP protein, which plays an important role in the efficient recruitment of MRE11. Reduced MRE11 recruitment correlates with improved replication fork stability.[52] The BRCA2-deficient tumor cells can also become resistant to PARP inhibitors by reducing the recruitment of a different nuclease, MUS81, to the stalled fork. Inhibition of the methyltransferase enhancer of EZH2 results in replication fork stabilization by limiting the recruitment of MUS81 nuclease.[57]

Fork structures also affect nucleolytic degradation of stalled replication forks. The reversed forks, which are formed in response to replication stress, are the entry point for replication fork degradation by MRE11 and exonuclease-1 (EXO1) nucleases.[58] The fork remodelers, zinc finger RANBP2-type containing-3 (ZRANB3), SWI/SNF-related matrix-associated actindependent regulator of chromatin subfamily A-like protein-1 (SMARCAL1), and helicase-like transcription factor (HLTF) promote MRE11-dependent replication fork degradation.[59] Loss of these factors can restore fork integrity in BRCA1/2-deficient cells.

Impaired replication-arrest-inactivation of SLFN11

Shlafen family member 11 (SLFN11) is a well-known determinant of cellular sensitivity to multiple anticancer agents that acts by damaging DNA including PARP inhibitors. Loss of SLFN11 alleviates PARP inhibitor toxicity in BRCA-proficient and BRCA2-deficient cells, which shows that SLFN11 acts in parallel with HR.[32],[60]

Upregulation of nuclear factor-κB signaling

Pathway analysis on the RNA sequencing data showed that nuclear factor κB (NF-κB) signaling is specifically upregulated in PARP inhibitor-resistant cells and that inhibition of core components in NF-κB signaling reverses the sensitivity to PARP inhibitors in resistant cells. Thus, upregulation of NF-κB signaling is one of the key mechanisms responsible for acquiring resistance to PARP inhibitors.[61] [Figure 4] shows various mechanisms of resistance to PARP inhibitors.
Figure 4: Multiple mechanisms of PARP inhibitor resistance[14]. BRCA1/2 = breast cancer gene 1/2; ORF = open reading frame; PARP1 = poly (adenosine diphosphate-ribose) polymerase 1; 53BP1 = 53 binding protein 1

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 » Overcoming Resistance to PARP Inhibitors Top

There is ongoing research on the development of drug combination strategies, which can selectively impair HR in cancer cells and subsequently sensitize HR-proficient cancers to PARP inhibitors. Multiple clinical trials are assessing combinations with PARP inhibitors to expand their use in the treatment of OC. These trials will address questions, including the ability to cause and inhibit DNA damage repair, forced apoptosis through dual DNA repair blockade, inducing BRCAness, and overcoming PARP inhibitor resistance.

Resistance associated with P-glycoprotein overexpression can be relatively easily overcome as some agents have low affinity to P-glycoprotein (e.g. veliparib). Thus, targeting P-glycoprotein activity in the context of PARP inhibitor resistance could be a highly effective approach to overcome therapy resistance, but further research is needed.[2]

Perhaps the most challenging mechanism of PARP inhibitor resistance is the secondary mutations that lead to BRCA1/2 reactivation. The HR-deficient tumors upregulate the microhomology-mediated end-joining (MMEJ) pathway.[62] Thus, combined treatment strategy of PARP inhibitors and key MMEJ factors, such as polymerase θ (POLQ), can form a synergistic approach to prolong patient response by preventing or delaying the emergence of resistant clones. Once the HR pathway is restored, sensitivity to PARP inhibitors can be reinstated via induction of a BRCAness phenotype.[60] Cyclin-dependent kinase-1 (CDK1) phosphorylates BRCA1, which is essential for efficient BRCA1 focus formation. Thus, depletion or inhibition of CDK1 compromises the cellular capacity to repair DNA by HR.[63] Similarly, inhibition of another CDK12 also results in suppression of HR. Similarly, inhibition of histone deacetylases (HDACs) results in downregulation of the HR pathway, which helps improve PARP inhibitor sensitivity.[64] As the function of HR relies on various pathways with signaling molecules, such as epidermal growth factor receptor (EGFR), insulin-like growth factor type 1 receptor (IGF1R), vascular endothelial growth factor receptor (VEGF), and phosphoinositide 3-kinase (PI3K), inhibition of either of these can be an attractive strategy to overcome the resistance to PARP inhibitors.[65] A subset of HR proteins, including RAD51, BRCA1, and BRCA2, are stabilized by heat shock protein 90 (HSP90). Stability of these proteins can be targeted by HSP90 inhibition or mild hypothermia to induce a HR-deficient-like state.[66] Thus, they can improve PARP inhibitor sensitivity and potentiate the PARP inhibitor efficacy.

Some loss-of-function mutations that cause PARP inhibitor resistance may result in increased sensitivity to other treatments. For example, loss of NHEJ factors results in hypersensitivity to ionizing radiation. Therefore, radiotherapy might be a viable option to treat PARP1/poly (ADPribose) glycohydrolase-deficient cancers or BRCA1-deficient tumors with a defective 53BP1 end-protection pathway.[32] The ATM/ATR kinases play central roles in coordinating cell cycle progression with DNA repair. The ATM kinase activity is essential for HR, and its inhibition resensitizes BRCA1-deficient cells that developed PARP inhibitor resistance through loss of 53BP1 or REV7.[67] ATR inhibition (ATRi) enforces unscheduled origin firing and increases replication fork breakage, resulting in genomic instability and apoptosis. A recent study demonstrated that ATRi can overcome PARP inhibitor resistance in cells with rewired HR and fork protection pathways.[50] ATR functions in parallel to SLFN11, and SLFN11-deficient cells solely rely on ATR signaling for their survival upon replicative DNA damage induced by PARP inhibitors. Thus, combining ATRi and PARP inhibitors could be a novel therapeutic strategy to treat SLFN11-deficient tumors.[58] Tumor cells with rewired fork protection might become more reliant on DNA damage tolerance mechanisms, such as the RAD6/RAD18-mediated SOS response.[32] Another possible resistance mechanism may be due to depletion of SMARCAL1 (a SNF2-family DNA translocase), which leads to restoring replication fork stability. This reduces the formation of replication stress-induced DNA breaks in BRCA1/2-deficient cells, which may eventually lead to PARP inhibitor resistance.[68]

Apart from these strategies, PARP inhibitor and tumor-associated immunosuppression provides evidence to support the combination of PARP inhibitors and programmed death-ligand-1 (PD-L1) or programmed cell death protein-1 (PD-1) immune checkpoint blockade as a potential therapeutic approach to treat breast cancer.[69] Combining epigenetic agents such as lysine-specific histone demethylase-1A inhibitors or HDAC inhibitors with PARP inhibitors/anti-PD-1/PD-L1 is another novel, potentially synergistic strategy for priming tumors and overcoming resistance.[3] [Table 2] summarizes various strategies that can overcome the resistance to PARP inhibitors.
Table 2: Strategies to overcome PARP inhibitor resistance

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 » Clinical Use of PARP inhibitors in Indian Patients Top

The burden of breast cancer and OCs is high in Indian women.[70] Olaparib is the only PARP inhibitor approved in India (August 2018). Currently, there is paucity of data in Indian patients who are on PARP inhibitors. In a single-center, single-arm study conducted in north India with 28 patients receiving PARP inhibitors, the overall response rate was 82% with complete response in five patients. The mean overall survival was 32.9 months and more than 70% of patients receiving PARP inhibitors eventually progressed.[71] With increased use, resistance to PARP inhibitors is an imminent threat. Understanding the causes for resistance and developing strategies to overcome resistance can pre-empt this and rationalize the management.

 » Conclusion Top

The PARP pathway and its inhibition constitute a therapeutic breakthrough for patients with ovarian and breast cancer. PARP inhibitor resistance is a growing concern and understanding the various mechanisms of resistance to PARP inhibitor can help develop new strategies to overcome it effectively. Additionally, it is necessary to identify the subset of patients who will obtain maximum benefit from PARP inhibitor therapy and assist in planning treatment strategies to overcome PARP inhibitor resistance in them. To broaden the therapeutic horizon of PARP inhibitors in the future, there is a need to use companion diagnostics to identify patients, find and validate biomarkers that predict HR deficiency and response to PARP inhibitors.

 » Acknowledgments Top

The authors would like to thank AstraZeneca Pharma India Ltd. for the development of this manuscript in collaboration with Ms. Prajakta Nachane M. Pharm., from Covance Scientific Services & Solutions Pvt. Ltd. in accordance with the GPP3 guidelines (http://www.

Financial support and sponsorship

AstraZeneca Pharma India Ltd.

Conflict of interest

Archita Joshi is an employee of AstraZeneca Pharma India Ltd.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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