The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy in Pancreatic Cancer Models by Altering Ribonucleotide Reductase Subunit-1 (RRM1)

Vena, Francesca; Causi, Eleonora Li; Rodriguez‐Justo, Manuel; Goodstal, Samantha; Hagemann, Thorsten; Hartley, John A.; Hochhauser, Daniel

doi:10.1158/1078-0432.ccr-15-0485

Cited by 51 publications

(37 citation statements)

References 45 publications

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“…Nonetheless, GEM treatment reduced viable Suit-2 T27N tumor cells by 4-fold compared to PBS-treated Suit-2 T27N tumors, and a similar fold reduction was seen in Suit-2 tumors treated with AZD6244 + GEM (Figure 4B). A recent study published by Vena et al [31] also showed that the efficacy of GEM treatment was enhanced in pancreatic cancer models when administered in combination with a MEK1/2 inhibitor, Pimasertib. This study proposed a mechanism independent of MV-release for the increased efficacy.…”

Section: Discussionmentioning

confidence: 99%

Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells

et al. 2016

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High mortality in pancreatic cancer patients is partly due to resistance to chemotherapy. We describe that human pancreatic cancer cells acquire drug resistance by a novel mechanism in which they expel and remove chemotherapeutic drugs from the microenvironment via microvesicles (MVs). Using human pancreatic cancer cells that exhibit varied sensitivity to gemcitabine (GEM), we show that GEM exposure triggers the cancer cells to release MVs in an amount that correlates with that cell line's sensitivity to GEM. The importance of MV-release in gaining drug resistance in GEM-resistant pancreatic cancer cells was confirmed when the inhibition of MV-release sensitized the cells to GEM treatment, both in vitro and in vivo. Mechanistically, MVs remove drugs that are internalized into the cells and that are in the microenvironment. The differences between the drug-resistant and drug-sensitive pancreatic cancer cell lines tested here are explained based on the variable content of influx/efflux proteins present on MVs, which directly dictates the ability of MVs either to trap GEM or to allow GEM to flow back to the microenvironment.

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Section: Discussionmentioning

confidence: 99%

Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells

et al. 2016

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“…It has shown potent activity in cell lines and xenografts with an activated MAPK pathway, robust antitumour activity in mouse models of myeloma and colorectal cancer, and to be able to circumvent resistance to BRAF inhibition in human melanoma cells . Notably, pimasertib has been shown to sensitise tumour cells to the effects of other anticancer agents and to work synergistically with gemcitabine to delay tumour growth in a pancreatic cancer mouse model …”

Section: Introductionmentioning

confidence: 99%

“…[17][18][19] It has shown potent activity in cell lines and xenografts with an activated MAPK pathway, 17,19,20 robust antitumour activity in mouse models of myeloma 17 and colorectal cancer, 19 and to be able to circumvent resistance to BRAF inhibition in human melanoma cells. 20 Notably, pimasertib has been shown to sensitise tumour cells to the effects of other anticancer agents 17,21 and to work synergistically with gemcitabine to delay tumour growth in a pancreatic cancer mouse model. 20 Given this preclinical evidence, a two-part study was designed to investigate pimasertib in combination with the standard-of-care therapy, gemcitabine, compared to gemcitabine alone as first-line treatment in patients with mPaCa.…”

Section: Introductionmentioning

confidence: 99%

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

Cutsem

Hidalgo²,

Canon

et al. 2018

Intl Journal of Cancer

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The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.

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“…Although hENT1 and RRM1 have been found to be associated with gemcitabine-resistant pancreatic cancer, the molecular mechanism remains to be elucidated. Previous reports have stated that Notch is involved in mediating hENT1 and RRM1, with PPARα and PPARγ mediating hENT1, AKT, phosphoinositide 3-kinase, RAS/ERT and mitogen-activated protein kinase kinase 1/2 mediating RRM1 (25–29). The present study investigated whether the EMT transcriptional factors, TWIST1 and Slug, can suppress the expression of hENT1 and enhance the expression of RRM1 in GR-HPCCs.…”

Section: Discussionmentioning

confidence: 99%

Sclareolide enhances gemcitabine-induced cell death through mediating the NICD and Gli1 pathways in gemcitabine-resistant human pancreatic cancer

Chen¹,

Wang

Zhang³

et al. 2017

Molecular Medicine Reports

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Pancreatic cancer is a type of cancer, which rapidly develops resistance to chemotherapy. Gemcitabine is the treatment used clinically, however, gemcitabine resistance leads to limited efficacy and patient survival rates of only a few months following diagnosis. The aim of the present study was to investigate the mechanisms underlying gemcitabine resistance in pancreatic cancer and to select targeted agents combined with gemcitabine to promote the treatment of pancreatic cancer. Panc-1 and ASPC-1 human pancreatic cancer cells (HPCCs) were used to establish the experimental model, and HPCCs were exposed to gemcitabine of serially increased concentrations to generate gemcitabine-resistant cells (GR-HPCCs). The anticancer effect of gemcitabine combined with sclareolide was then assessed. Epithelial to mesenchymal transition (EMT), human equilibrative nucleoside transporter 1 (hENT1) and ribonucleoside diphosphate reductase 1 (RRM1) were detected in the HPCCs and GR-HPCCs, and the mechanisms were investigated. Sclareolide resensitized the GR-HPCCs to gemcitabine. The expression levels of hENT1 and RRM1 were lower and higher, respectively, in GR-HPCCs, compared with HPCCs. Sclareolide upregulated hENT1, downregulated RRM1 and inhibited gemcitabine-induced EMT through the TWIST1/Slug pathway in the GR-HPCCs. In addition, sclareolide mediated the NOTCH 1 intracellular cytoplasmic domain (NICD)/glioma-associated oncogene 1 (Gli1) pathway, which triggered TWIST1/Slug-hENT1/RRM1 signaling and resensitized GR-HPCCs to gemcitabine. Finally, sclareolide resensitized GR-HPCCs to gemcitabine through inducing apoptosis; in vivo, the co-administraion of sclareolide and gemcitabine effectively suppressed tumor growth. Sclareolide may be a novel agent in combination with gemcitabine for the treatment of gemcitabine-resistant pancreatic cancer, which resensitizes GR-HPCCs to gemcitabine through mediating NICD and Gli1.

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The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy in Pancreatic Cancer Models by Altering Ribonucleotide Reductase Subunit-1 (RRM1)

Cited by 51 publications

References 45 publications

Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells

Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells

Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer

Sclareolide enhances gemcitabine-induced cell death through mediating the NICD and Gli1 pathways in gemcitabine-resistant human pancreatic cancer

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