cdr

Hot Keywords
Drug Resistance Mechanisms Epigenetic Resistance in Cancer Therapy Biomarkers Pharmacogenetics of Cancer Liquid Biopsy Targeted Cancer Therapy Non-coding RNAs Kinase Inhibitors ABC Transporters

Top
Cancer Drug Resist 2022;5:637-46. 10.20517/cdr.2021.146 © The Author(s) 2022.
Open Access Commentary

Ovarian cancer resistance to PARPi and platinum-containing chemotherapy

Department of Obstetrics and Gynecology, Division Gynecologic Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Correspondence to: Dr. Rebekah Summey, Department of Obstetrics and Gynecology, Division Gynecologic Oncology, Medical College of Wisconsin, 8701 West Watertown Plank Rd., Milwaukee, WI 53226, USA. E-mail: rsummey@mcw.edu

    This article belongs to the Special Issue Memory of Franco Muggia:Drug Resistance in Female Cancer
    Views:235 | Downloads:66 | Cited:0 | Comments:0 | :0
    Academic Editors: Godefridus J. Peters, Cristisiana Sessa, Andrea Bonetti | Copy Editor: Jia-Xin Zhang | Production Editor: Jia-Xin Zhang

    © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

    Abstract

    Epithelial ovarian cancer remains the most lethal female malignancy despite options for systemic therapy and the emergence of targeted therapies. Although initial response to therapy is observed, recurrence and ultimately chemoresistance result in overall therapeutic failure. This pattern has been evident with platinum therapy since the 1980s. Significant excitement surrounded the approval of poly (ADP-ribose) polymerase inhibition (PARPi) as a novel therapeutic option, especially with the advent of personalized medicine, but resistance has similarly developed to these treatments. Novel agents are constantly being sought, but if the obstacle of chemoresistance remains, the durability of responses will remain tenuous. Unraveling the multifactorial mechanisms of platinum and PARPi resistance is increasingly important as a therapeutic failure with current strategies is almost assured. Focusing greater efforts on expanding the current understanding of the complex nature of platinum and PARPi chemoresistance has tremendous potential to improve clinical outcomes.

    EPITHELIAL OVARIAN CANCER AND THE LIMITATIONS OF CURRENT THERAPY

    Epithelial ovarian cancer (EOC), primarily high-grade serous carcinoma (HGSOC), remains the leading cause of death from gynecologic cancers primarily due to the advanced stage at the time of diagnosis and the inherent difficulty of treating tumors that become resistant to chemotherapy over varying amounts of time. Surgical cytoreduction and platinum-based chemotherapy have been the mainstay of ovarian cancer treatment since the 1980s. Platinum cytotoxicity results from its ability to cause an accumulation of deoxyribonucleic acid (DNA) double-strand breaks and cell death via the formation of intra-strand and inter-strand adducts which activate cellular DNA damage response (DDR) pathways, which inhibit replication and transcription of DNA, inducing cell cycle arrest and apoptosis[1]. Platinum-based therapy has been the cornerstone of EOC treatment for decades, but the majority of patients relapse within two years, and eventual platinum resistance is accompanied by an extremely poor prognosis[2,3]. Platinum-refractory disease is defined as a persistent or progressive disease while receiving platinum-based chemotherapy or within four weeks of therapy, and platinum resistance is defined as cancer recurrence or progression within six months of platinum therapy[3]. The median survival in platinum-resistant disease is only 12 months, underscoring the need to identify novel therapies but also to understand and overcome the complex mechanisms of chemoresistance[4].

    The advent of poly (ADP-ribose) polymerase inhibition (PARPi) as a novel therapeutic option approved for EOC in 2014 presented significant excitement and marked the birth of personalized medicine in EOC. Poly (ADP-ribose) polymerases (PARP) are a family of proteins with several roles that include DNA repair (including nucleotide excision repair, non-homologous end joining, homologous recombination (HR) and DNA mismatch repair), apoptosis, chromatin remodeling and the stress response[5]. Several clinical trials have demonstrated the impressive benefit of PARPi therapy, especially in patients who have responded to platinum-based therapy[6,7]. This might be attributable to the high prevalence of tumors with homologous recombination deficiency (HRD), which is found in approximately 50% of all ovarian cancers[6]. BReast CAncer gene (BRCA1/2) germline deficiency accounts for approximately 20% of these cases[4]. Somatic BRCA mutations result in HGSOC phenotypes and platinum chemotherapy responses similar to germline BRCA mutation carriers and are referred to as HGSOC with “BRCAness”. BRCA variants, either germline or somatic, lead to an increased susceptibility to DNA double-strand breaks. PARPi elegantly capitalizes on synthetic lethality when PARP inhibition and HRD are combined to cause apoptosis of cancer cells[8].

    Resistance to platinum therapy is strongly predictive of resistance to PARPi therapy consistent with overlapping biologic mechanisms of susceptibility and resistance[2,9]. A specific definition for PARPi resistance has not yet been developed as exists for platinum-based chemotherapy, and it remains to be seen if tumors are resistant to all PARPi once resistance is developed to a single PARPi[6].

    In this commentary, we will explain some of the most clinically relevant tumor biology contributing to platinum and PARPi resistance, two of the most significant therapies in use currently for EOC, as well as review future directions.

    MECHANISMS OF CHEMORESISTANCE

    There are several mechanisms, both intrinsic and acquired, that contribute to platinum chemoresistance. Platinum compounds may undergo decreased uptake into cells, increased efflux, or increased inactivation. For example, overexpression of the adenosine triphosphate-binding cassette (ABC) family of transporters, such as P-glycoprotein or multidrug resistance-related proteins (MRP1), affects the efflux of chemotherapeutic drugs. Although the exact mechanism of action is not clear, high levels of ABC subfamily A member 1 expression have been found to correlate with poor progression-free and overall survival in serous EOC[10].

    Once platinum cytotoxicity has occurred and adducts have begun to form, cells may still be able to thwart its effects by acquiring the ability to repair platinum-induced DNA adducts via counteraction of the cell’s DDR response. The DDR response is an essential network of proteins that sense, signal and/or repair DNA damage to maintain genomic integrity and stability within the cell[11]. Key proteins that signal DNA damage to cell-cycle checkpoints and DNA repair pathways include: ataxia-telangiectasia mutated (ATM), ATM-and RAD3-related, DNA-dependent protein kinases[6]. These key proteins sense DNA damage and initiate repair signaling cascades by phosphorylation of key repair proteins: BRCA1, checkpoint kinase 1 (CHK1), checkpoint kinase 2, tumor protein p53 (P53) and RAD17[12]. Cellular mechanisms that assist in the repair of DNA include base excision repair for single-strand breaks (SSBs); nucleotide excision repair (NER) for the repair of bulky adducts (such as observed with platinum therapy); mismatch repair (MMR) for mispaired bases; homologous recombination (HR) repair for double-stranded breaks (DSBs), intra-strand and inter-strand crosslinks; non-homologous end-joining (NHEJ) for DSB; or microhomology-mediated end joining for the repair of DSBs[13].

    When DNA damage is too severe for repair, apoptosis is triggered[13]. Cells that have acquired platinum resistance subvert the normal DDR responses and instead demonstrate increased ability to initiate repair signaling, activate checkpoints to slow progression and allow repair, increase the pace of adduct repair or even develop the ability to tolerate DNA adducts without resorting to apoptosis[1,14].

    The NER and HR repair pathways work very closely together. The NER pathway recognizes and removes bulky helix-distorting crosslink lesions via a step-wise process: damage recognition, unwinding of the DNA locally around damage, incision of damaged DNA by endonucleases, and DNA resynthesis and ligation[15]. This process allows NER to recognize DNA crosslinks and converts the crosslink to a DNA double-strand break. HR is then required to repair the double-strand break to prevent apoptosis[16].

    In preclinical trials, enhanced NER in ovarian cancer models has been associated with increased cisplatin resistance in vitro, supporting the importance of NER in the development of platinum chemoresistance[17,18,19]. Specifically, the excision repair cross-complementation group 1 (ERCC1) protein plays a key role in nucleotide excision repair. Dimerization of ERCC1 with xeroderma pigmentosum complementation group F (XPF) enables excision and repair of bulky cisplatin lesions in damaged DNA[18]. Overexpression of proteins in the NER pathway, including ERCC1, is associated with platinum resistance, likely via the ERCC1-XPF endonuclease[19,20].

    Additionally, P53 expression, common in HGSOC, promotes tumorigenesis as well as drug resistance via inhibition of apoptosis. Inhibited apoptosis contributes to proliferation and metastasis[2]. P53 expression specifically leads to growth phase 1 (G1) / synthesis (S) checkpoint deficiencies and cell-cycle dysregulation, subsequently placing greater stress on the growth phase 2 (G2) / mitosis (M) checkpoint for survival. Wee1 kinase inhibits activation of Cyclin-dependent kinases 1 (CDK1) and CDK2, making it a key cell cycle regulator of the G2/M transition. Alterations in Wee1 kinase may have implications for chemoresistance[21].

    Although the majority of EOC responds to platinum therapy, even if only for a limited time, many do not exhibit any durable response to platinum therapy. Mechanisms of such intrinsic chemoresistance include proficient DNA repair, cyclin E1 (CCNE1) amplification, and mesenchymal or proliferative molecular subtypes. Approximately 20% of EOC cases have CCNE1 amplification, which are associated with primary resistance to platinum[22].

    The current understanding of the mechanism of PARPi resistance centers around Darwinian escape. Darwinian escape refers to an acquired secondary somatic mutation to restore HR in BRCA 1/2 (reversion mutations)[7]. BRCA reversion mutations have been identified in progression biopsies as well as cell-free DNA (cfDNA). cfDNA has shown polyclonality of multiple reversion mutations within a single patient when under pressure from treatment[8]. One mutation that has demonstrated restoration of DNA repair is BRCA1-Δ11q. Patients with BRCA1-Δ11q demonstrated decreased sensitivity to both cisplatin and PARPi[23]. BRCA reversion mutations have been identified in 13% of patients with platinum-refractory disease and 18% of patients with platinum-resistant disease[5]. Patients with BRCA reversion mutations experienced decreased progression-free survival when undergoing treatment with rucaparib[24]. The initial strength of response to PARPi has been shown to correlate with the severity of eventual tumor resistance[5].

    TUMOR MICROENVIRONMENT AND METABOLISM IMPACT ON CHEMORESISTANCE

    Numerous studies have demonstrated the critical role of hypoxia in the tumor microenvironment and its association with platinum resistance via signaling pathways in DNA damage, mitochondrial activity, apoptosis autophagy, and drug efflux[25,26]. Chen et al.[27] demonstrated that cisplatin-resistant cancer cells show increased intracellular hypoxia and decreased glucose uptake suggesting that platinum resistance might stem from alterations in glucose metabolism. Altered angiogenesis is another hallmark of intra-tumor vessels which also contributes to hypoxia, poor drug delivery, and chemoresistance[28].

    Cancer-associated fibroblasts, tumor-associated macrophages, and cancer stem cells have all been proposed influencers of prognosis and chemotherapy resistance. Stromal activation with extensive desmoplasia has been associated with poor clinical outcomes and acquired treatment resistance[27,29]. Platinum chemotherapy is also thought to influence anti-tumor immunity. Increased infiltration of immunosuppressive Cluster of Differentiation 163-positive macrophages and increased infiltration of regulatory forkhead box P3-positive T cells have favored tumor growth[6,30-32]. In contrast, the presence of tumor-infiltrating lymphocytes is positively correlated with survival[6,33]. Data on immune checkpoint therapy in EOC has been contradictorily reflecting an incomplete understanding of the key regulators and pathways[6]. Immunotherapy may yet play an important role in EOC.

    Additionally, the omentum and cell metabolism are thought to play a pivotal role in cancer progression and chemoresistance. The omentum is a favored site for metastasis due to EOC’s ability to use fatty acids to initiate and sustain peritoneal metastasis; in addition, it may also participate in ascites formation[34,35]. Elevated cytokines and adipokines in the ascitic fluid are thought to protect malignant cells from chemotherapy-induced apoptosis, including via lysophosphatidic acid signaling and prostaglandin E2 -mediated GFTR transporter upregulation[19]. The metabolism of tumor cells is intricately intertwined with all cells of the microenvironment. Tumor cells have demonstrated an amazing ability to metabolically adjust to changes in their environment, as well as influence the metabolic function of neighboring cells for their own purposes[34,35,36].

    Cancer stem cells (CSCs) are theorized as a population of cells capable of self-renewal and repopulation following cancer treatment that may cause tumor initiation and metastasis[37]. Stem cell pathways have recently been recognized as an important mediator of chemoresistance. CSCs have improved methods of chemotherapy removal from the cell, including the ABC cassette and drug transporters. Tumors containing heterogeneous cancer cells are linked to progression as they are more likely to undergo selection towards a population of drug-resistant tumor cells with treatment. CSCs are aided by their microenvironment and stimulated by hypoxia-inducible factors. Phosphoinositide kinase (PI3K) has an important role in apoptosis for maintaining stem cell “stemness” and drug resistance. Notch signaling and Wnt/beta-catenin are important in CSCs signaling pathways and may be useful targets[38]. CSCs are also able to grow in spheres and expand as sphere-like cellular aggregates more easily than other populations of cells[39]. The ability to treat cancer stem cells is of particular importance since these cells can remain in patients with seemingly no evidence of disease or lead to metastasis.

    FUTURE DIRECTIONS

    Chemoresistance evolves over time as a response to the selective pressure of therapy. The multiple mechanisms of resistance are complex and not fully understood, but strategies to overcome chemoresistance are being developed. These methods include exploration of methods to improve drug delivery; identification of potentially useful biomarkers; identification of molecular targets; and exploitation of tumor weaknesses using modulation of the cell cycle, tumor microenvironment, or cellular metabolism. Combination therapies may improve this exploitation of tumor weaknesses.

    Drug delivery

    Improved drug delivery could also combat chemoresistance. Nanotechnology is being used to investigate the ability of nanoparticles to improve targeted treatment, including the encapsulation of cisplatin with dendrimers to aid in cell killing[2,40]. Layer-by-layer nanoparticles have also been used to deliver cisplatin and a PARPi to mice, with improved bioavailability, cytotoxicity, and systemic toxicity compared with conventionally administered medication[40]. Natural compounds including curcumin and piperine are being evaluated to attempt to induce G2/M phase arrest, caspase activation, the PI3K pathway (piperine), and apoptosis and phosphorylation of p53 (curcumin)[2].

    Biomarkers

    A study of patients with durable responses may be useful for identifying biomarkers, especially patients with HR proficiency who have good responses[7]. Improved understanding of why some patients with BRCA pathogenic variants do not respond to PARPi, and why some patients with no known BRCA mutation respond to PARPi treatment could be important for combatting drug resistance. Biomarkers that predict treatment success would be of significant benefit if they allowed improved treatment selection. However, our understanding of biomarkers that would be useful in guiding treatment selection is limited. A number of genes and proteins have been identified in patients with chemoresistance or poor prognosis and have yet to be evaluated in clinical trials to guide treatment. One gene amplification, 19q12, is associated with chemoresistance and has been identified in 20% of ovarian cancer patients[3,40]. MMR deficiency has also been implicated in chemoresistance, but the correlation is controversial[3,19,41].

    Based on the leading roles played by ERCC1 and XPF in the NER pathway, they have been promising prospects as biomarkers for platinum-based therapy. A meta-analysis of retrospective in vitro studies in non-small cell lung cancer by Altaha et al.[42] concluded that high levels of ERCC1-mRNA and/or ERCC1 protein were associated with resistance to platinum compounds. Despite the correlation between ERCC1 overexpression with platinum resistance and ERCC1 under expression with platinum sensitivity, translating ERCC1 as a predictive biomarker for response to platinum-based therapy in clinical trials has been challenging[43]. ERCC1 has been investigated as a biomarker in both adrenocortical carcinomas and advanced non-small cell lung cancer and did not offer prognostic or treatment selection benefits[44,45]. Continued study of ERCC1 and the NER pathway is needed.

    Patients with PARPi resistance have been found to have reversions in RAD51C and RAD51D, and in vitro studies have demonstrated loss of TP53 binding protein 1[3,46]. Studies of TP53 vary regarding its utility as a marker in platinum resistance, but it may be helpful in treatment planning[47]. Pump P-glycoprotein (P-gp) expression, which is related to drug efflux and multidrug resistance, has also been implicated in PARPi resistance[3,48]. CSC markers of Bmi-1, Nanog and Oct 4 with elevated stem cell factor and c-Kit levels indicated chemoresistance as well[37]. Other proteins indicating resistance and poor prognosis include Notch3 and LGR5; CD24 correlates with poor prognosis, chemoresistance, metastasis, and recurrence; CD44+/CD117+ cells were associated with chemoresistance; CD133+ cells showed cisplatin resistance, and ALDH1A1 was associated with poor survival and drug resistance[36,49]. AT-rich interaction domain 1A inactivation or loss of expression is also correlated with poor overall survival in patients receiving platinum. Micro ribonucleic acids (miRNAs), including let-7 g, miR-98-5p, miR-622 as well as others, have been associated with platinum and/or PARPi resistance[50].

    Newer technology in tumor surveillance may also be critical to the understanding of tumor chemoresistance and the discovery of biomarkers. Liquid biopsies may offer a unique opportunity for real-time tumor molecular profiling. Liquid biopsies enable the analysis of circulating tumor cells, circulating tumor DNA, circulating mRNA, and tumor-derived extracellular vesicles that are shed from primary tumors into the peripheral blood[51]. Serial assessments would enable real-time patient assessment and comparison during therapy at the onset of resistance to therapy, which may increase our understanding of chemoresistance.

    Genetics

    Other possible areas of investigation involve the utilization of next-generation sequencing to aid the discovery of predictive signatures. Four molecular subtypes of HGSOC have been described and validated by the Cancer Genome Atlas Research Network study[52]. Absolute copy number profiles have been generated using primary and relapsed HGSC samples. Macintyre et al.[53] identified seven copy number signatures that were stable between diagnosis and disease relapse, indicating that copy number signatures at diagnosis may predict overall survival and platinum resistance[54]. Different mutational processes generate unique combinations of mutation types, termed mutational signatures[55]. The Catalogue of Somatic Mutations in Cancer (COSMIC) has revealed many mutational signatures across the spectrum of human cancer types. Analysis of COSMIC mutational signatures in ovarian cancer reveals a prevalence of signature 1B[56].

    Epigenetic modifications are mechanisms that alter the expression of a gene but do not change the DNA sequence. These modifications help to regulate normal genome functioning. Epigenetic modifications may also be contributing to chemoresistance. Identification of epigenetic changes in chemoresistant EOC may allow for the advanced development of epigenetic modulating drug therapy. Current agents such as demethylating agents, histone deacetylase inhibitors, and microRNA-targeting therapies have shown preclinical promise[57].

    Homologous recombination and combination therapies

    Defining PARPi resistance and evaluating the utility of alternating PARPi therapy if resistance has developed to one PARP remains to be seen but may be answered by the OReO trial[6,58]. PARPi do have different potencies due to the degree of PARP trapping; clinical implications have yet to be seen. Additionally, re-examining the definition of platinum sensitivity and resistance may be needed.

    Combination therapies of PARPi and platinum together, or the addition of another agent to combat chemoresistance when using one or the other, may allow circumvention of treatment resistance. In a study by Gajan et al.[58] of breast cancer patients with and without BRCA mutations and with resistance to both cisplatin and olaparib, a benefit of combined therapy with olaparib and cisplatin was identified. Interestingly, the combination treatment was not helpful in patients whose disease was still sensitive to either treatment[59]. A similar investigation could be considered in EOC patients as well. Niraparib has been investigated in combination with carboplatin and gemcitabine for patients with unresectable or recurrent platinum-sensitive ovarian cancer and showed a 57% radiographic response rate[60]. Cisplatin-resistant ovarian cancer cells (C13) were treated with a PARPi, 3-aminobenzamide by Zhang et al.[60] Cellular proliferation was inhibited more when treated with cisplatin and increasing doses of PARPi, pointing to chemosensitization[61]. Additional studies investigating novel DDR-targeting agents and combination treatment approaches are underway.

    As targetable pathways have been implicated in chemoresistance, translational researchers have also been searching for immunotherapies and molecular targets to use as combination therapies to improve the cytotoxic effect of therapy. Anti-angiogenesis with cediranib in combination with olaparib has been investigated with efficacy that varied by mutation identified following PARPi progression, with poorer outcomes identified for patients with HRD reversion mutations and ABCB1 upregulation[62]. This treatment combination is under further investigation with the OVC2 trial[6,63]. One promising target for therapeutics to combine with PARPi is mesenchymal-epithelial transition factor (c-Met), a receptor tyrosine kinase, since the high expression is associated with a poor prognosis. This biomarker and therapeutic target have been linked to PARP resistance and HR restoration[7]. CDK have also been proposed as targets since they control cell cycle progression and DNA damage control. Loss of CDK inhibition impairs BRCA function (BRCAness)[7]. PI3K inhibitors have been proposed as methods to extend the use of PARPi and are under investigation[7,64,65]. Other therapies that have been trialed include PARPi with alkylating agents, topoisomerase I inhibitors, WEE1 kinase inhibitors, PI3K inhibitors, radiation, immunotherapy, and DNA methyltransferase inhibitors. PARPi with topoisomerase I inhibitor allows inhibition of TOP1-PARylation, inhibition of homologous recombination and stimulation of NHEJ plus inhibition of tyrosyl-DNA-phosphodiesterase I. Clinical investigations of this combination have not been completed[5]. However, promising combination treatments to overcome PARPi or platinum resistance have not been identified.

    CONCLUSIONS

    EOC is a disease marked by frequent relapses and responses to therapy before the eventual development of chemoresistance. Chemoresistance remains a steadfast obstacle to improving EOC survival. Platinum, the mainstay of EOC treatment, is limited by almost ubiquitous platinum resistance. While anti-angiogenic therapy and PARPi are promising new treatments, resistance has already been observed. The heterogeneity of EOC allows it to adapt in response to treatment and confounds attempts to identify clinically meaningful biomarkers and targets. Tumors constantly evolving with time and treatment seem to naturally develop resistance.

    In some cancers, real-time collection of circulating tumor DNA is a reality that has enabled the characterization of drug response for tumors along with multiple time points[62]. EOC, given its inherent heterogeneity, may require an equally malleable treatment approach: the serial integration of genomic, epigenomic, metabolomic, and immunogenic study at diagnosis and at each recurrence to optimize therapy. It would require a significant change in clinical practice and greater investment in bioinformatics, but it may not be possible to conquer all the nuances of EOC without it.

    DECLARATIONS

    Authors’ contributions

    Made substantial contributions to the conception and design of this study, performed literature review, wrote and edited the manuscript: Summey R

    Conceived and designed this study, performed literature review, co-wrote and edited the manuscript: Uyar D

    Availability of data and materials

    Not applicable.

    Financial support and sponsorship

    None.

    Conflicts of interest

    All authors declared that there are no conflicts of interest.

    Ethical approval and consent to participate

    Not applicable.

    Consent for publication

    Not applicable.

    Copyright

    © The Author(s) 2022.

    References

    • 1. Damia G, Broggini M. Platinum resistance in ovarian cancer: role of DNA repair. Cancers (Basel) 2019;11:119.

      DOIPubMed PMC
    • 2. McFadden M, Singh SK, Oprea-Ilies G, Singh R. Nano-based drug delivery and targeting to overcome drug resistance of ovarian cancers. Cancers (Basel) 2021;13:5480.

      DOIPubMed PMC
    • 3. Freimund AE, Beach JA, Christie EL, Bowtell DDL. Mechanisms of drug resistance in high-grade serous ovarian cancer. Hematol Oncol Clin North Am 2018;32:983-96.

      DOIPubMed
    • 4. Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-15.

      DOI
    • 5. Rose M, Burgess JT, O'Byrne K, Richard DJ, Bolderson E. PARP inhibitors: clinical relevance, mechanisms of action and tumor resistance. Front Cell Dev Biol 2020;8:564601.

      DOIPubMed PMC
    • 6. McMullen M, Karakasis K, Madariaga A, Oza AM. Overcoming platinum and PARP-inhibitor resistance in ovarian cancer. Cancers (Basel) 2020;12:1607.

      DOIPubMed PMC
    • 7. Klotz DM, Wimberger P. Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies? Arch Gynecol Obstet 2020;302:1087-102.

      DOIPubMed PMC
    • 8. Chiappa M, Guffanti F, Bertoni F, Colombo I, Damia G. Overcoming PARPi resistance: preclinical and clinical evidence in ovarian cancer. Drug Resist Updat 2021;55:100744.

      DOIPubMed
    • 9. Jiang X, Li X, Li W, Bai H, Zhang Z. PARP inhibitors in ovarian cancer: sensitivity prediction and resistance mechanisms. J Cell Mol Med 2019;23:2303-13.

      DOIPubMed PMC
    • 10. Hedditch EL, Gao B, Russell AJ, et al. Australian Ovarian Cancer Study Group. ABCA transporter gene expression and poor outcome in epithelial ovarian cancer. J Natl Cancer Inst 2014;106:dju149.

      DOIPubMed PMC
    • 11. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature 2009;461:1071-8.

      DOIPubMed PMC
    • 12. Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response. Mol Cell 2017;66:801-17.

      DOIPubMed
    • 13. Friedberg EC. A brief history of the DNA repair field. Cell Res 2008;18:3-7.

      DOIPubMed
    • 14. Galluzzi L, Senovilla L, Vitale I, et al. Molecular mechanisms of cisplatin resistance. Oncogene 2012;31:1869-83.

      DOIPubMed
    • 15. Costa RM, Chiganças V, Galhardo Rda S, Carvalho H, Menck CF. The eukaryotic nucleotide excision repair pathway. Biochimie 2003;85:1083-99.

      DOIPubMed
    • 16. Stergiou L, Eberhard R, Doukoumetzidis K, Hengartner MO. NER and HR pathways act sequentially to promote UV-C-induced germ cell apoptosis in caenorhabditis elegans. Cell Death Differ 2011;18:897-906.

      DOIPubMed PMC
    • 17. Martin LP, Hamilton TC, Schilder RJ. Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 2008;14:1291-5.

      DOIPubMed
    • 18. Duan M, Ulibarri J, Liu KJ, Mao P. Role of nucleotide excision repair in cisplatin resistance. Int J Mol Sci 2020;21:9248.

      DOIPubMed PMC
    • 19. Ferry KV, Hamilton TC, Johnson SW. Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF. Biochem Pharmacol 2000;60:1305-13.

      DOIPubMed
    • 20. Selvakumaran M, Pisarcik DA, Bao R, Yeung AT, Hamilton TC. Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res 2003;63:1311-6.

      PubMed
    • 21. Ha DH, Min A, Kim S, et al. Antitumor effect of a WEE1 inhibitor and potentiation of olaparib sensitivity by DNA damage response modulation in triple-negative breast cancer. Sci Rep 2020;10:9930.

      DOIPubMed PMC
    • 22. Cummings M, Freer C, Orsi NM. Targeting the tumour microenvironment in platinum-resistant ovarian cancer. Semin Cancer Biol 2021;77:3-28.

      DOIPubMed
    • 23. Wang Y, Bernhardy AJ, Cruz C, et al. kConFab Investigators. The BRCA1-Δ11q alternative splice isoform bypasses germline mutations and promotes therapeutic resistance to PARP INhibition and cisplatin. Cancer Res 2016;76:2778-90.

      DOIPubMed PMC
    • 24. Lin KK, Harrell MI, Oza AM, et al. .

      DOIPubMed
    • 25. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 2008;8:180-92.

      DOIPubMed
    • 26. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4:437-47.

      DOIPubMed
    • 27. Chen J, Wang X, Yuan Y, et al. Exploiting the acquired vulnerability of cisplatin-resistant tumors with a hypoxia-amplifying DNA repair-inhibiting (HYDRI) nanomedicine. Sci Adv 2021;7:eabc5267.

      DOIPubMed PMC
    • 28. Sahoo SS, Zhang XD, Hondermarck H, Tanwar PS. The emerging role of the microenvironment in endometrial cancer. Cancers (Basel) 2018;10:408.

      DOIPubMed PMC
    • 29. Patch AM, Christie EL, Etemadmoghadam D, et al. Australian Ovarian Cancer Study Group. Whole-genome characterization of chemoresistant ovarian cancer. Nature 2015;521:489-94.

      DOIPubMed
    • 30. Ojalvo LS, Thompson ED, Wang TL, et al. Tumor-associated macrophages and the tumor immune microenvironment of primary and recurrent epithelial ovarian cancer. Hum Pathol 2018;74:135-47.

      DOIPubMed
    • 31. Martin de la Fuente L, Westbom-Fremer S, Arildsen NS, et al. PD-1/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma. Virchows Arch 2020;477:83-91.

      DOIPubMed PMC
    • 32. Sato E, Olson SH, Ahn J, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A 2005;102:18538-43.

      DOIPubMed PMC
    • 33. Hwang WT, Adams SF, Tahirovic E, Hagemann IS, Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. Gynecol Oncol 2012;124:192-8.

      DOIPubMed PMC
    • 34. Zhao G, Cardenas H, Matei D. Ovarian cancer-why lipids matter. Cancers (Basel) 2019;11:1870.

      DOIPubMed PMC
    • 35. Etzerodt A, Moulin M, Doktor TK, et al. Tissue-resident macrophages in omentum promote metastatic spread of ovarian cancer. J Exp Med 2020;217:e20191869.

      DOIPubMed PMC
    • 36. Ladanyi A, Mukherjee A, Kenny HA, et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 2018;37:2285-301.

      DOIPubMed PMC
    • 37. Chen RR, Yung MMH, Xuan Y, et al. Targeting of lipid metabolism with a metabolic inhibitor cocktail eradicates peritoneal metastases in ovarian cancer cells. Commun Biol 2019;2:281.

      DOIPubMed PMC
    • 38. Pieterse Z, Amaya-Padilla MA, Singomat T, et al. Ovarian cancer stem cells and their role in drug resistance. Int J Biochem Cell Biol 2019;106:117-26.

      DOIPubMed
    • 39. Chen X, Zhang J, Zhang Z, Li H, Cheng W, Liu J. Cancer stem cells, epithelial-mesenchymal transition, and drug resistance in high-grade ovarian serous carcinoma. Hum Pathol 2013;44:2373-84.

      DOIPubMed PMC
    • 40. Mensah LB, Morton SW, Li J, et al. Layer-by-layer nanoparticles for novel delivery of cisplatin and PARP inhibitors for platinum-based drug resistance therapy in ovarian cancer. Bioeng Transl Med 2019;4:e10131.

      DOIPubMed PMC
    • 41. Etemadmoghadam D, deFazio A, Beroukhim R, et al. AOCS Study Group. Integrated genome-wide DNA copy number and expression analysis identifies distinct mechanisms of primary chemoresistance in ovarian carcinomas. Clin Cancer Res 2009;15:1417-27.

      DOIPubMed PMC
    • 42. Altaha R, Liang X, Yu JJ, Reed E. Excision repair cross complementing-group 1: gene expression and platinum resistance. Int J Mol Med 2004;14:959-70.

      PubMed
    • 43. Helleman J, van Staveren IL, Dinjens WN, et al. Mismatch repair and treatment resistance in ovarian cancer. BMC Cancer 2006;6:201.

      DOIPubMed PMC
    • 44. Laufs V, Altieri B, Sbiera S, et al. ERCC1 as predictive biomarker to platinum-based chemotherapy in adrenocortical carcinomas. Eur J Endocrinol 2018;178:181-8.

      DOIPubMed
    • 45. Lee SM, Falzon M, Blackhall F, et al. Randomized prospective biomarker trial of ERCC1 for comparing platinum and nonplatinum therapy in advanced non-small-cell lung cancer: ERCC1 trial (ET). J Clin Oncol 2017;35:402-11.

      DOIPubMed
    • 46. Dabholkar M, Bostick-Bruton F, Weber C, Bohr VA, Egwuagu C, Reed E. ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients. J Natl Cancer Inst 1992;84:1512-7.

      DOIPubMed
    • 47. Kondrashova O, Nguyen M, Shield-Artin K, et al. AOCS Study Group. Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov 2017;7:984-98.

      DOIPubMed PMC
    • 48. Khan MA, Vikramdeo KS, Sudan SK, et al. Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management. Semin Cancer Biol 2021;77:99-109.

      DOIPubMed PMC
    • 49. Lawlor D, Martin P, Busschots S, et al. PARP inhibitors as P-glyoprotein substrates. J Pharm Sci 2014;103:1913-20.

      DOIPubMed
    • 50. Tothill RW, Tinker AV, George J, et al. Australian Ovarian Cancer Study Group. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 2008;14:5198-208.

      DOIPubMed
    • 51. Lianidou E, Pantel K. Liquid biopsies. Genes Chromosomes Cancer 2019;58:219-32.

      DOIPubMed
    • 52. Konecny GE, Wang C, Hamidi H, et al. Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. J Natl Cancer Inst 2014;106:dju249.

      DOIPubMed PMC
    • 53. Macintyre G, Goranova TE, De Silva D, et al. Copy number signatures and mutational processes in ovarian carcinoma. Nat Genet 2018;50:1262-70.

      DOIPubMed PMC
    • 54. COSMIC 2021. Mutational Signatures. Available from: https://cancer.sanger.ac.uk/signatures/ [Last accessed on 20 Apr 2022].

    • 55. Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Australian Pancreatic Cancer Genome Initiative. Signatures of mutational processes in human cancer. Nature 2013;500:415-21.

      DOIPubMed PMC
    • 56. Matthews BG, Bowden NA, Wong-Brown MW. Epigenetic mechanisms and therapeutic targets in chemoresistant high-grade serous ovarian cancer. Cancers (Basel) 2021;13:5993.

      DOIPubMed PMC
    • 57. U.S. National Library of Medicine. A study to examine olaparib maintenance retreatment in patients with epithelial ovarian cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT03106987 [Last accessed on 20 Apr 2022].

    • 58. Gajan A, Sarma A, Kim S, Gurdziel K, Wu GS, Shekhar MP. Analysis of adaptive olaparib resistance effects on cisplatin sensitivity in triple negative breast cancer cells. Front Oncol 2021;11:694793.

      DOIPubMed PMC
    • 59. Gray HJ, Bell-McGuinn K, Fleming GF, et al. Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies. Gynecol Oncol 2018;148:507-14.

      DOIPubMed
    • 60. Zhang J, Kan Y, Tian Y, Wang Z. Effects of poly (ADP-ribosyl) polymerase (PARP) inhibitor on cisplatin resistance & proliferation of the ovarian cancer C13* cells. Indian J Med Res 2013;137:527-32.

      PubMed PMC
    • 61. Lheureux S, Oaknin A, Garg S, et al. EVOLVE: a multicenter open-label single-arm clinical and translational phase II trial of cediranib plus olaparib for ovarian cancer after PARP inhibition progression. Clin Cancer Res 2020;26:4206-15.

      DOIPubMed
    • 62. U.S. National Library of Medicine. Testing the combination of cediranib and olaparib in comparison to each drug alone or other chemotherapy in recurrent platinum-resistant ovarian cancer. Available from: https://clinicaltrials.gov/ct2/show/NCT02502266. [Last accessed on 20 Apr 2022].

      DOI
    • 63. Matulonis UA, Wulf GM, Barry WT, et al. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Ann Oncol 2017;28:512-8.

      DOIPubMed PMC
    • 64. Konstantinopoulos PA, Barry WT, Birrer M, et al. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. The Lancet Oncology 2019;20:570-80.

      DOIPubMed PMC
    • 65. Attard G, Swennenhuis JF, Olmos D, et al. Characterization of ERG, AR and PTEN gene status in circulating tumor cells from patients with castration-resistant prostate cancer. Cancer Res 2009;69:2912-8.

      DOIPubMed

    Cite This Article

    Summey R, Uyar D. Ovarian cancer resistance to PARPi and platinum-containing chemotherapy. Cancer Drug Resist 2022;5:637-46. http://dx.doi.org/10.20517/cdr.2021.146

    Views
    235
    Downloads
    66
    Citations
     0
    Comments
    0

    0

    Comments

    Comments must be written in English. Spam, offensive content, impersonation, and private information will not be permitted. If any comment is reported and identified as inappropriate content by OAE staff, the comment will be removed without notice. If you have any queries or need any help, please contact us at support@oaepublish.com.

    Article Access Statistics

    • Viewed: 235
    • Downloaded: 66
    • Cited: Crossref0

    Share This Article

    See Updates

    © 2016-2022 OAE Publishing Inc., except certain content provided by third parties