Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models

Handley, Katelyn F.; Rodríguez-Aguayo, Cristian; Ma, Shaolin; Stur, Elaine; Joseph, Robiya; Bayraktar, Emine; Nguyen, Nghi; Powell, Reid T.; Sobieski, Mary; Ivan, Cristina; Kim, Mark Seungwook; Umamaheswaran, Sujanitha; Glassman, Deanna; Wen, Yunfei; Amero, Paola; Stephan, Clifford; Coleman, Robert L.; Landesman, Yosef; Westin, Shannon N.; Ram, Prahlad T.; Sood, Anil K.

doi:10.1158/1535-7163.mct-21-0370

Cited by 10 publications

(7 citation statements)

References 46 publications

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“…This approach effectively minimizes the false-negative rate and maximizes the chance of detecting synergistic interactions when compared with a single-point or fixed-ratio experimental approach. To provide additional rigor and automated outlier detection, the data were fit to a 3D surface using a support vector machine-based method as described previously [ 39 ]. The theoretical additivity surface was then calculated using a Bliss independence model [ 40 ].…”

Section: Methodsmentioning

confidence: 99%

Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo

et al. 2023

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Metastatic colorectal cancer (mCRC) is the second leading cause of cancer deaths in the United States. More than 50% of patients with mCRC harbor mutations of the oncogenic driver RAS (KRAS or NRAS). Because directly targeting most mutations of RAS is technically challenging, researchers have concentrated on targeting MEK, a downstream mediator of RAS. However, targeting MEK as single-agent therapy is ineffective in patients with mCRC. We hypothesize that combining a MEK inhibitor with other agents can enhance the efficacy of MEK targeting in mCRC. Unbiased high-throughput screening (HTS) was performed to identify drugs that enhance the efficacy of MEK inhibitors. HTS was performed with KRAS-mutated CRC cells using the MEK inhibitor trametinib as a “backbone” and two “clinically ready” compound libraries approved by the U.S. Food and Drug Administration or in clinical trials. HTS demonstrated that the combination of the SRC inhibitor dasatinib and trametinib was synergistic in CRC cells in vitro (MTT and colony formation assays). Analysis of markers for cell proliferation and apoptosis using fluorescence-activated cell sorting, reverse-phase protein array, or Western blotting demonstrated decreased cell proliferation and increased cell death when targeting both SRC and MEK as compared to single agents in multiple CRC cell lines. However, combining dasatinib and trametinib in vivo at doses in mice equivalent to doses used in humans failed to significantly enhance the antitumor activity of trametinib when compared to that of trametinib alone. These results underscore the importance of performing careful preclinical in vivo validation studies using clinically relevant doses as a prerequisite for translating in vitro findings to the clinic.

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Section: Methodsmentioning

confidence: 99%

Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo

et al. 2023

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“…These agents have also been demonstrated to significantly inhibit tumour proliferation in human ovarian carcinoma xenografts and orthotopic models. 114,196,209,210 KPT-330 in combination with cisplatin exhibited an enhanced tumour-suppressing effect on platinum-sensitive ovarian cancer cells. These synergistic effects work by boosting platinum sensitivity in these cancer cells.…”

Section: Ovarian Cancermentioning

confidence: 96%

“…The combination of KPT-330 with topotecan or olaparib significantly decreases tumour nodule size, inhibits tumour cell proliferation and extends survival in vivo. 196,209,210 To address the issue of tumour cell resistance caused by the long-term use of SINEs, strategies such as inhibiting the NRG1/EBB3 signalling pathway have shown potential effectiveness. 211…”

Section: Ovarian Cancermentioning

confidence: 99%

“…In vitro A Bcl-xL inhibitor in vitro 184 Ovarian cancer Both 315 Decitabine in vitro 325 ; an inhibitor of MDM2-p53 interaction in vitro 209 ; cisplatin in vitro and vivo 315,326 ; olaparib in vitro and vivo 327 Prostate cancer Both 309 Abiraterone in vitro 214 ; enzalutamide in vitro and vivo 322,214 ; DTX in vitro and vivo 318 ; cisplatin in vitro and vivo 322 Sarcoma Both BORT in vitro and vivo 328 Gastrointestinal stromal tumours Both 216 Imatinib in vitro 216 Liposarcoma Both 221 Carfilzomib in vitro 329 Dedifferentiated liposarcoma Both 216 NR Sarcoma of soft part of alveolar Both 216…”

Section: Cervical Cancermentioning

confidence: 99%

“…In addition, KPT‐330 combined with other drugs, such as RG7388 (an MNM2 inhibitor) or olaparib, synergistically impedes ovarian cancer cell proliferation in vitro by promoting apoptosis. The combination of KPT‐330 with topotecan or olaparib significantly decreases tumour nodule size, inhibits tumour cell proliferation and extends survival in vivo 196,209,210 . To address the issue of tumour cell resistance caused by the long‐term use of SINEs, strategies such as inhibiting the NRG1/EBB3 signalling pathway have shown potential effectiveness 211 …”

Section: The Study Of Sine Compounds In Various Solid Tumoursmentioning

confidence: 99%

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The nuclear export protein exportin‐1 in solid malignant tumours: From biology to clinical trials

Lai,

Xu,

Dai

2024

Clinical & Translational Med

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BackgroundExportin‐1 (XPO1), a crucial protein regulating nuclear‐cytoplasmic transport, is frequently overexpressed in various cancers, driving tumor progression and drug resistance. This makes XPO1 an attractive therapeutic target. Over the past few decades, the number of available nuclear export‐selective inhibitors has been increasing. Only KPT‐330 (selinexor) has been successfully used for treating haematological malignancies, and KPT‐8602 (eltanexor) has been used for treating haematologic tumours in clinical trials. However, the use of nuclear export‐selective inhibitors for the inhibition of XPO1 expression has yet to be thoroughly investigated in clinical studies and therapeutic outcomes for solid tumours.MethodsWe collected numerous literatures to explain the efficacy of XPO1 Inhibitors in preclinical and clinical studies of a wide range of solid tumours.ResultsIn this review, we focus on the nuclear export function of XPO1 and results from clinical trials of its inhibitors in solid malignant tumours. We summarized the mechanism of action and therapeutic potential of XPO1 inhibitors, as well as adverse effects and response biomarkers.ConclusionXPO1 inhibition has emerged as a promising therapeutic strategy in the fight against cancer, offering a novel approach to targeting tumorigenic processes and overcoming drug resistance. SINE compounds have demonstrated efficacy in a wide range of solid tumours, and ongoing research is focused on optimizing their use, identifying response biomarkers, and developing effective combination therapies.Key Points Exportin‐1 (XPO1) plays a critical role in mediating nucleocytoplasmic transport and cell cycle. XPO1 dysfunction promotes tumourigenesis and drug resistance within solid tumours. The therapeutic potential and ongoing researches on XPO1 inhibitors in the treatment of solid tumours. Additional researches are essential to address safety concerns and identify biomarkers for predicting patient response to XPO1 inhibitors.

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Mechanism and rational combinations with GP‐2250, a novel oxathiazine derivative, in ovarian cancer

Kim,

Glassman,

Handley

et al. 2024

Cancer Medicine

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BackgroundGP‐2250, a novel analog of taurultam (TRLT), has emerged as a potent anti‐neoplastic drug; however, the mechanisms underlying its effects are not well understood. Here, we investigated the mechanism of action and the biological effects of GP‐2250 using in vitro and in vivo models.MethodsWe carried out a series of in vitro (MTT assay, Annexin V/PI assay, colony formation assay, reverse‐phase protein array [RPPA], and HRLC/IC analysis) to determine the biological activity of GP‐2250 and investigate the mechanism of action. In vivo experiments were carried out to determine the therapeutic efficacy of GP‐2250 alone and in combination with standard‐of‐care drugs (e.g., paclitaxel, cisplatin, topotecan, and poly ADP‐ribose polymerase [PARP] inhibitors).ResultsWe investigated the cytotoxic effect of GP‐2250 in 10 ovarian cancer cell lines and found GP‐2250 combined with a PARP inhibitor had the greatest synergy. RPPA revealed that GP‐2250 inhibited hypoxia‐inducible factor‐1α, AKT, and mammalian target of rapamycin (mTOR) activation and expression. High‐resolution mass spectrometry revealed that hexokinase2 activity and protein expression were significantly reduced by GP‐2250 exposure. Furthermore, GP‐2250 reduced glycolysis and ATP synthesis in cancer cells. An in vivo pharmacodynamic experiment using the OVCAR8 mouse model demonstrated that 500 mg/kg GP‐2250 was effective in downregulating AKT and mTOR activation and expression. In the in vivo therapy experiment using an orthotopic mouse model, a combination of GP‐2250 with either PARP inhibitors or bevacizumab showed a significant reduction of tumor weights and nodules compared to those treated with a vehicle, control IgG groups, or monotherapy groups.ConclusionsTaken together, our data indicate that GP‐2250 exerts profound effects on tumor metabolism and, in combination with PARP inhibitors or bevacizumab, showed promising anti‐tumor efficacy. These findings could have implications for the clinical development of GP‐2250.

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Rational Combination of CRM1 Inhibitor Selinexor and Olaparib Shows Synergy in Ovarian Cancer Cell Lines and Mouse Models

Cited by 10 publications

References 46 publications

Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo

Combining MEK and SRC inhibitors for treatment of colorectal cancer demonstrate increased efficacy in vitro but not in vivo

The nuclear export protein exportin‐1 in solid malignant tumours: From biology to clinical trials

Mechanism and rational combinations with GP‐2250, a novel oxathiazine derivative, in ovarian cancer

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