Dual Inhibition of PI3K-AKT-mTOR- and RAF-MEK-ERK-signaling is synergistic in cholangiocarcinoma and reverses acquired resistance to MEK-inhibitors

Ewald, Florian; Nörz, Dominik; Grottke, Astrid; Hofmann, Bianca T.; Nashan, Björn; Jücker, Manfred

doi:10.1007/s10637-014-0149-7

Cited by 51 publications

(46 citation statements)

References 44 publications

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“…Dual inhibition of AKT and MTOR with MK-2206 and everolimus (RAD001) has been shown to enhance anti-proliferative effects in CCA [73]. More recently, increased efficacy was attained in-vitro by dual inhibition of the PI3K/AKT/MTOR and RAF/MEK/ERK pathway, which overcame resistance pathways [74].…”

Section: Less-established Molecular Aberrationsmentioning

confidence: 99%

The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets

Chong

Zhu

2016

Oncotarget

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Cholangiocarcinoma (CCA) is a relatively rare malignancy that arises from the epithelial cells of the intrahepatic, perihilar and distal biliary tree. Intrahepatic CCA (ICC) represents the second most common primary liver cancer, after hepatocellular cancer. Two-thirds of the patients with ICC present with locally advanced or metastatic disease. Despite standard treatment with gemcitabine and cisplatin, prognosis remains dismal with a median survival of less than one year. Several biological plausibilities can account for its poor clinical outcomes. First, despite the advent of next generation and whole exome sequencing, no oncogenic addiction loops have been validated as clinically actionable targets. Second, the anatomical, pathological and molecular heterogeneity, and rarity of CCA confer an ongoing challenge of instituting adequately powered clinical trials. Last, most of the studies were not biomarker-driven, which may undermine the potential benefit of targeted therapy in distinct subpopulations carrying the unique molecular signature. Recent whole genome sequencing efforts have identified known mutations in genes such as epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog (BRAF) and tumor protein p53 (TP53), novel mutations in isocitrate dehydrogenase (IDH), BRCA1-Associated Protein 1 (BAP1) and AT-rich interactive domain-containing protein 1A (ARID1A), and novel fusions such as fibroblast growth factor receptor 2 (FGFR2) and ROS proto-oncogene 1 (ROS1). In this review, we will discuss the evolving genetic landscape of CCA, with an in depth focus on novel fusions (e.g. FGFR2 and ROS1) and somatic mutations (e.g. IDH1/2), which are promising actionable molecular targets.

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Section: Less-established Molecular Aberrationsmentioning

confidence: 99%

The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets

Chong

Zhu

2016

Oncotarget

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“…This indicates that the mitochondrial apoptotic pathway is activated preferentially by ARS4. The PI3K/AKT and MAPK/ERK pathways are mediators of cell growth and survival (Asati et al, 2016, Ewald et al, 2014, Saini et al, 2013). For both types of cells, ARS4 treatment resulted in a dose-dependent inactivation of the PI3K/AKT and MAPK/ERK pathways as reflected by reduced total AKT and dephosphorylation of AKT, mTOR, and ERK (Fig.…”

Section: Resultsmentioning

confidence: 99%

Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer

Zhang

Liu

et al. 2016

EBioMedicine

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Artemisinin (ARS) and its derivatives, which are clinically used antimalarial agents, have shown antitumor activities. Their therapeutic potencies, however, are limited by their low solubility and poor bioavailability. Here, through a pharmacophore hybridization strategy, we synthesized ARS-drug conjugates, in which the marketed chemotherapeutic agents chlorambucil, melphalan, flutamide, aminoglutethimide, and doxifluridine, were separately bonded to Dihydroartemisinin (DHA) through various linkages. Of these, the artemisinin-melphalan conjugate, ARS4, exhibited most toxicity to human ovarian cancer cells but had low cytotoxicity to normal cells. ARS4 inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis, and inhibition of migration; these effects were stronger than those of its parent drugs, DHA and melphalan. Furthermore, ARS4 modulated the expression of proteins involved in cell cycle progression, apoptosis, and the epithelial–mesenchymal transition (EMT). Moreover, in mice, ARS4 inhibited growth and intraperitoneal dissemination and metastasis of ovarian cancer cells without observable toxic effects. Our results provide a basis for development of the compound as a chemotherapeutic agent.Research in contextArtemisinin compounds have recently received attention as anticancer agents because of their clinical safety profiles and broad efficacy. However, their therapeutic potencies are limited by low solubility and poor bioavailability. Here, we report that ARS4, an artemisinin-melphalan conjugate, possesses marked in-vitro and in-vivo antitumor activity against ovarian cancer, the effects of which are stronger than those for its parent drugs, Dihydroartemisinin and melphalan. In mice, ARS4 inhibits localized growth of ovarian cancer cells and intraperitoneal dissemination and metastasis without appreciable host toxicity. Thus, for patients with ovarian cancer, ARS4 is a promising chemotherapeutic agent.

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“…Prior in vitro work suggests that PI3K/AKT inhibition can Combination Targeting of AKT and MEK Pathways in Prostate Cancer result in up-regulation of the Raf/MEK/ERK pathway [36], and our results in the MR49F xenograft model also suggests this may occur in some cases. The well-recognized crosstalk between these pathways provides a rationale for combining both of these inhibitors [19][20][21][22][37][38][39]. Clinical experience with dual targeting of MEK and AKT pathways is limited; early results in advanced malignancies suggests that dual targeting of both pathways improves oncologic efficacy at the cost of greater toxicity [40].…”

Section: Discussionmentioning

confidence: 99%

“…Combined targeting of the MEK and AKT pathway has been investigated in several other cancers in pre-clinical models, with results supporting the use of the combination [19][20][21][22][37][38][39]. In a pre-clinical prostate cancer in vivo study, PD0325901 was assessed in combination with the mTOR inhibitor rapamycin [14].…”

Section: Discussionmentioning

confidence: 99%

Combined Akt and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer.

Toren¹,

Kim²,

Fazli³

et al. 2016

JCO

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Despite recent improvements in patient outcomes using newer androgen receptor (AR) pathway inhibitors, treatment resistance in castrate resistant prostate cancer (CRPC) continues to remain a clinical problem. Co-targeting alternate resistance pathways are of significant interest to treat CRPC and delay the onset of resistance. Both the AKT and MEK signaling pathways become activated as prostate cancer develops resistance to AR-targeted therapies. This pre-clinical study explores co-targeting these pathways in AR-positive prostate cancer models. Using various in vitro models of prostate cancer disease states including androgen dependent (LNCaP), CRPC (V16D and 22RV1) and ENZ-resistant prostate cancer (MR49C and MR49F), we evaluate the relevance of targeting both AKT and MEK pathways. Our data reveal that AKT inhibition induces apoptosis and inhibits cell growth in PTEN null cell lines independently of their sensitivity to hormone therapy; however, AKT inhibition had no effect on the PTEN positive 22RV1 cell line. Interestingly, we found that MEK inhibition had greater effect on 22RV1 cells compared to LNCaP, V16D or ENZ-resistant cells MR49C and MR49F cells. In vitro, combination AKT and MEK blockade had evidence of synergy observed in some cell lines and assays, but this was not consistent across all results. In vivo, the combination of AKT and MEK inhibition resulted in more consistent tumor growth inhibition of MR49F xenografts and longer disease specific survival compared to AKT inhibitor monotherapy. As in our in vitro study, 22RV1 xenografts were more resistant to AKT inhibition while they were more sensitive to MEK inhibition. Our results suggest that targeting AKT and MEK in combination may be a valuable strategy in prostate cancer when both pathways are activated and further support the importance of characterizing the dominant oncogenic pathway in each patient's tumor in order to select optimal therapy.

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Dual Inhibition of PI3K-AKT-mTOR- and RAF-MEK-ERK-signaling is synergistic in cholangiocarcinoma and reverses acquired resistance to MEK-inhibitors

Abstract: AKT, mTOR and MEK are promising targets for a combinatorial treatment of cholangiocarcinoma cells even after acquisition of MEK inhibitor resistance.

Cited by 51 publications

References 44 publications

The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets

The landscape of targeted therapies for cholangiocarcinoma: current status and emerging targets

Preclinical Efficacy and Safety Assessment of Artemisinin-Chemotherapeutic Agent Conjugates for Ovarian Cancer

Combined Akt and MEK pathway blockade in pre-clinical models of enzalutamide-resistant prostate cancer.

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