Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

Busschots, Steven; O’Toole, Sharon; O’Leary, John; Stordal, Britta K.

doi:10.1016/j.yexcr.2014.12.001

Cited by 16 publications

(14 citation statements)

References 66 publications

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“…Resistant variants were found to be cross-resistant to docetaxel, doxorubicin, vinorelbine and depsipeptide, which are known MDR1 substrates (Fig S2B). Cells remained sensitive to carboplatin as single agent, consistent with the low dose used and its established mechanism of action (Busschots et al, 2015). Extended drug-free culturing for >4 months resulted in partial reversal of paclitaxel + carboplatin resistance (Fig S2C–F), suggesting transient mechanisms in addition to stable changes.…”

Section: Resultsmentioning

confidence: 64%

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

et al. 2017

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Summary Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin chemoresistance models and identified a 35-gene resistance signature, which associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug resistant cells progressively increased expression of many JumonjiC demethylases, had altered histone methylation and importantly showed hypersensitivity to JumonjiC inhibitors, in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naïve cells and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin chemoresistant NSCLCs.

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Section: Resultsmentioning

confidence: 64%

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

et al. 2017

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“…OVCAR8 cells have been previously shown to have reduced BRCA-1 expression attributed to promoter methylation and are sensitive to DNA-damaging agents (36)(37)(38). Strikingly, the genetic deletion of PARP1 in EOC cells with a BRCA1 mutation or BRCA1 promoter methylation did not result in synthetic lethality, in that the cells were viable and grew in culture (21,39).…”

Section: Crispr/cas9 Deletion Of Parp1 In Ovarian Cancer Cellsmentioning

confidence: 97%

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

Makvandi

Pantel

Schwartz

et al. 2018

Journal of Clinical Investigation

100

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50% of patients with HRD respond to PARPi therapy (3). Moreover, patients without known HRD have also shown a clinical benefit from PARPis, as seen in recent trials assessing niraparib, olaparib, or rucaparib, as maintenance therapy in platinum-sensitive recurrent ovarian cancer (5-8). Given that not all patients will respond to PARPi therapy, improved clinical tools for predicting which patients will respond are urgently needed.Numerous clinical trials have led to FDA approval of 3 PARPis since 2014 and there is continued development of 2 additional drugs within this class (9-13). Despite growth in the BACKGROUND. Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of patients with ovarian cancer; however, resistance caused by low enzyme expression of the drug target PARP-1 remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel PET imaging agent. METHODS.We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer. First, we produced PARP1-KO ovarian cancer cell lines using CRISPR/Cas9 gene editing to test the loss of PARP-1 as a resistance mechanism to all clinically used PARP inhibitors. Next, we performed preclinical microPET imaging studies using ovarian cancer patient-derived xenografts in mouse models. Finally, in a phase I PET imaging clinical trial we explored PET imaging as a regional marker of PARP-1 expression in primary and metastatic disease through correlative tissue histology. RESULTS.We found that deletion of PARP1 causes resistance to all PARP inhibitors in vitro, and microPET imaging provides proof of concept as an approach to quantify PARP-1 in vivo. Clinically, we observed a spectrum of standard uptake values (SUVs) ranging from 2-12 for PARP-1 in tumors. In addition, we found a positive correlation between PET SUVs and fluorescent immunohistochemistry for PARP-1 (r 2 = 0.60).CONCLUSION. This work confirms the translational potential of a PARP-1 PET imaging agent and supports future clinical trials to test PARP-1 expression as a method to stratify patients for PARP inhibitor therapy.TRIAL REGISTRATION. Clinicaltrials.gov NCT02637934. 22-24). Furthermore, PARP-1 has been development and application of PARPis, the primary drug target poly(ADP-ribose) polymerase 1 (PARP-1) has never been evaluated in vivo, even though loss of expression in vitro is a wellcharacterized resistance mechanism (3,(14)(15)(16)(17)(18)(19). It was first hypothesized that PARPis work primarily through a synthetic lethality pathway where loss of BRCA1 or BRCA2 combined with chemical inhibition of PARP-1 results in cell death (20, 21). However, it was later shown that deletion of PARP1 did not result in BRCA1-restored cells showed no increase in γH2AX compared with DMSO controls. Olaparib-treated OVCAR8 PARP1-KO G1 and G3 cells showed a 1.3 times increase (ANOVA, **P < 0.01 and ***P < 0.001, respectively) in γH2AX...

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“…Veliparib (ABT‐888) is a potent, orally bioavailable poly(ADP‐ribose) polymerase (PARP)‐1/2 inhibitor that may increase the efficacy of chemotherapeutic regimens by delaying DNA repair after chemotherapy‐induced damage . In preclinical models, veliparib enhanced the activity of cisplatin, carboplatin and cyclophosphamide, whereas cell lines that quickly develop resistance to taxanes and carboplatin retained their sensitivity to veliparib, thus supporting the candidacy of this agent for the treatment of platinum‐resistant or taxane‐resistant ovarian cancer . In phase 1 clinical trials, veliparib, either as a single‐agent therapy or in combination with cyclophosphamide or carboplatin and paclitaxel, had an acceptable tolerability profile.…”

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confidence: 99%

Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer

et al. 2017

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This phase 1, open‐label, dose‐escalation study was conducted to determine the safety, tolerability, pharmacokinetics and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg b.i.d. on days 1–21 with carboplatin (area under the concentration–time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m2 on days 1, 8 and 15 every 3 weeks for up to 6 21‐day cycles. Dose escalation followed a 3 + 3 design to determine dose‐limiting toxicities, maximum tolerated dose and the recommended phase 2 dose. Nine patients (median age 62 [range 27–72] years) received a median of 5 (range 3–6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose‐limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer.

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Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells

Abstract: . (2015) Carboplatin and taxol resistance develops more rapidly in functional BRCA1 compared to dysfunctional BRCA1 ovarian cancer cells.

Cited by 16 publications

References 66 publications

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer

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