A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097

Jeay, Sébastien; Gaulis, Swann; Ferretti, Stéphane; Bitter, Hans; Ito, Moriko; Valat, Thérèse; Murakami, Masato; Ruetz, Stephan; Guthy, Daniel; Rynn, Caroline; Jensen, Michael Rugaard; Wiesmann, Marion; Kallen, Joerg; Furet, Pascal; Gessier, François; Holzer, Philipp; Masuya, Keiichi; Würthner, Jens U.; Halilovic, Ensar; Hofmann, Francesco; Sellers, William R.; Porta, Diana Graus

doi:10.7554/elife.06498

Cited by 73 publications

(102 citation statements)

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“…wild type cells was demonstrated before by Jeay et al [15] . Another human NET cell line, KRJ-1, has also been reported to harbor a nonmutated TP53 gene and to be sensitive to treatment with the MDM2 inhibitor nutlin-3 [18,19] .…”

Section: Discussionmentioning

confidence: 54%

“…Several small molecule MDM2 inhibitors including NVP-CGM097 (NCT01760525, Novartis) have entered clinical phase I trials (online suppl. Table. 1) [11][12][13][14][15] .…”

Section: Discussionmentioning

confidence: 99%

“…The small molecule inhibitor NVP-CGM097 is a novel MDM2 inhibitor [15][16][17] which binds to human MDM2 with a K i value of 1.3 n M [15] . We investigated the In contrast, p53 mutated BON1 and p53 mutated NCI-H727 tumor cells were insensitive to NVP-CGM097.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of MDM2 by small molecules seems to be a promising novel strategy for targeted therapy in oncology [11][12][13][14] . The small molecule inhibitor NVP-CGM097 is a novel MDM2 inhibitor [15][16][17] which binds to human MDM2 with a K i value of 1.3 n M [15] .…”

Section: Introductionmentioning

confidence: 99%

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The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

et al. 2016

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Background/Aims: The tumor suppressor p53 is depleted in many tumor cells by the E3 ubiquitin ligase mouse double minute 2 homolog (MDM2) through MDM2/p53 interaction. A novel target for inhibiting p53 degradation and for causing reexpression of p53^{wild type} is inhibition of MDM2. The small molecule NVP-CGM097 is a novel MDM2 inhibitor. We investigated MDM2 inhibition as a target in neuroendocrine tumor cells in vitro. Methods: Human neuroendocrine tumor cell lines from the pancreas (BON1), lung (NCI-H727), and midgut (GOT1) were incubated with the MDM2 inhibitor NVP-CGM097 (Novartis) at concentrations from 4 to 2,500 nM. Results: While p53^{wild type} GOT1 cells were sensitive to NVP-CGM097, p53^mutated BON1 and p53^mutated NCI-H727 cells were resistant to NVP-CGM097. Incubation of GOT1 cells with NVP-CGM097 at 100, 500, and 2,500 nM for 96 h caused a significant decline in cell viability to 84.9 ± 9.2% (p < 0.05), 77.4 ± 6.6% (p < 0.01), and 47.7 ± 9.2% (p < 0.01). In a Western blot analysis of GOT1 cells, NVP-CGM097 caused a dose-dependent increase in the expression of p53 and p21 tumor suppressor proteins and a decrease in phospho-Rb and E2F1. Experiments of co-incubation of NVP-CGM097 with 5-fluorouracil, temozolomide, or everolimus each showed additive antiproliferative effects in GOT1 cells. NVP-CGM097 and 5-fluorouracil increased p53 and p21 expression in an additive manner. Conclusions: MDM2 inhibition seems a promising novel therapeutic target in neuroendocrine tumors harboring p53^{wild type}. Further investigations should examine the potential role of MDM2 inhibitors in neuroendocrine tumor treatment.

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Section: Discussionmentioning

confidence: 54%

“…Several small molecule MDM2 inhibitors including NVP-CGM097 (NCT01760525, Novartis) have entered clinical phase I trials (online suppl. Table. 1) [11][12][13][14][15] .…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

et al. 2016

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“…4 Previously, MDM2 antagonism efficacy modeling was analyzed using large oncology cell line panels, with resulting multi-marker algorithms associated with response. 5,6 In vitro MDM2 antagonist activity associated with a 4-gene panel (MDM2, XPC, CDKN2A /p16, BBC3/PUMA), each regulated by p53, was validated in AML clinical studies with previous (RG7112) and current (idasanutlin [RG7388]) MDM2 antagonists in clinical development. 5 Interestingly, in an analysis of blood specimens from patients with AML, none of the 4 genes alone showed significant association with patient outcomes following treatment with MDM2 antagonists.…”

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confidence: 99%

Acute myeloid leukemia patients clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts

et al. 2016

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Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent

et al. 2017

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The SCLC combination screen examined a 9‐point concentration response of 180 third agents, alone and in combination with etoposide/carboplatin. The predominant effect of adding a third agent to etoposide/carboplatin was additivity. Less than additive effects occurred frequently in SCLC lines sensitive to etoposide/carboplatin. In SCLC lines with little or no response to etoposide/carboplatin, greater than additive SCLC killing occurred over the entire spectrum of SCLC lines but never occurred in all SCLC lines. Exposing SCLC lines to tubulin‐targeted agents (paclitaxel or vinorelbine) simultaneously with etoposide/carboplatin resulted primarily in less than additive cell killing. As single agents, nuclear kinase inhibitors including Aurora kinase inhibitors, Kinesin Spindle Protein/EG5 inhibitors, and Polo‐like kinase‐1 inhibitors were potent cytotoxic agents in SCLC lines; however, simultaneous exposure of the SCLC lines to these agents along with etoposide/carboplatin, generally, resulted in less than additive cell killing. Several classes of agents enhanced the cytotoxicity of etoposide/carboplatin toward the SCLC lines. Exposure of the SCLC lines to the MDM2 inhibitor JNJ‐27291199 produced enhanced killing in 80% of the SCLC lines. Chk‐1 inhibitors such as rabusertib increased the cytotoxicity of etoposide/carboplatin to the SCLC lines in an additive to greater than additive manner. The combination of GSK‐3β inhibitor LY‐2090314 with etoposide/carboplatin increased killing in approximately 40% of the SCLC lines. Exposure to the BET bromodomain inhibitor MK‐8628 increased the SCLC cell killing by etoposide/carboplatin in 20–25% of the SCLC lines. Only 10–15% of the SCLC lines had an increased response to etoposide/carboplatin when simultaneously exposed to the PARP inhibitor talazoparib.

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A distinct p53 target gene set predicts for response to the selective p53–HDM2 inhibitor NVP-CGM097

Cited by 73 publications

References 53 publications

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

The HDM2 (MDM2) Inhibitor NVP-CGM097 Inhibits Tumor Cell Proliferation and Shows Additive Effects with 5-Fluorouracil on the p53-p21-Rb-E2F1 Cascade in the p53<sup>wild type</sup> Neuroendocrine Tumor Cell Line GOT1

Acute myeloid leukemia patients clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts

Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent

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