Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models

Hu, Chaoxin; Dadon, Tikva; Chenna, Venugopal; Yabuuchi, Shinichi; Bannerji, Rajat; Booher, Robert; Strack, Peter R.; Azad, Nilofer A.; Nelkin, Barry D.; Maitra, Anirban

doi:10.1158/1535-7163.mct-15-0028

Cited by 53 publications

(37 citation statements)

References 60 publications

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“…Dinaciclib and MK-2206 have previously been shown to be active against pancreatic adenocarcinoma (37). In KRAS mutant pancreatic cancer patient derived xenografts, Hu and colleagues demonstrated efficacy of dinaciclib combined with MK-2206.…”

Section: Discussionmentioning

confidence: 99%

Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition

Au-Yeung

Lang

Azar

et al. 2017

Clinical Cancer Research

127

102

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Purpose Cyclin E1 (CCNE1) amplification is associated with primary treatment resistance and poor outcome in high grade serous ovarian cancer (HGSC). Here, we explore approaches to target CCNE1 amplified cancers and potential strategies to overcome resistance to targeted agents. Experiment Design To examine dependency on CDK2 in CCNE1 amplified HGSC, we utilised siRNA and conditional shRNA gene suppression, and chemical inhibition using dinaciclib, a small molecule CDK2 inhibitor. High throughput compound screening was used to identify selective synergistic drug combinations, as well as combinations that may overcome drug resistance. An observed relationship between CCNE1 and the AKT pathway was further explored in genomic data from primary tumors, and functional studies in fallopian tube secretory cells. Results We validate CDK2 as a therapeutic target by demonstrating selective sensitivity to gene suppression. However, we found that dinaciclib did not trigger amplicon-dependent sensitivity in a panel of HGSC cell lines. A high throughput compound screen identified synergistic combinations in CCNE1 amplified HGSC, including dinaciclib and AKT inhibitors. Analysis of genomic data from TCGA demonstrated co-amplification of CCNE1 and AKT2. Over-expression of Cyclin E1 and AKT isoforms, in addition to mutant TP53, imparted malignant characteristics in untransformed fallopian tube secretory cells, the dominant site of origin of HGSC. Conclusions These findings suggest a specific dependency of CCNE1 amplified tumors for AKT activity, and point to a novel combination of dinaciclib and AKT inhibitors that may selectively target patients with CCNE1 amplified HGSC.

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Section: Discussionmentioning

confidence: 99%

Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition

Au-Yeung

Lang

Azar

et al. 2017

Clinical Cancer Research

127

102

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“…Currently, several small molecule inhibitors of Akt have been developed and are in various stages of clinical testing (33). For instance, in combination with a cyclin-dependent kinase inhibitor (dinaciclib), the oral pan-AKT Inhibitor MK-2206 can dramatically block pancreatic tumor growth and metastases in patient-derived xenograft models (34). Phase I trial results of MK-2206 in patients with advanced solid tumors indicate that MK-2206 was well tolerated, with evidence of Akt signaling blockade (35).…”

Section: Discussionmentioning

confidence: 99%

HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy

et al. 2016

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Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). Genome-wide association studies have suggested the little studied gene HEATR1 as a possible determinant of cellular sensitivity to different chemotherapeutic drugs. In this study, we assessed this hypothesized link in PDAC, where HEATR1 expression is downregulated significantly. HEATR1 silencing in PDAC cells increased resistance to gemcitabine and other chemotherapeutics, where this effect was associated with increased AKT kinase phosphorylation at the Thr308 regulatory site. Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as a scaffold to facilitate interactions between AKT and the protein phosphatase PP2A, thereby promoting Thr308 de-phosphorylation. Consistent with these findings, treatment with the AKT inhibitor TCN sensitized HEATR1-depleted PDAC cells to gemcitabine, suggesting this therapeutic combination may overcome gemcitabine resistance in patients with low HEATR1 expression. Clinically, we found that HEATR1 downregulation in PDAC patients was associated with increased AKT phosphorylation, poor response to tumor resection plus gemcitabine standard-of-care treatment and shorter overall survival. Collectively, our findings establish HEATR1 as a novel regulator of AKT and a candidate predictive and prognostic indicator of drug responsiveness and outcome in PDAC patients.

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“…Moreover, a recent phase I clinical trial reported partial responses in 54% of patients with relapsed or refractory CLL 124 . Interestingly, dinaciclib synergized with the AKT inhibitor MK-2206 and caused strong tumour growth inhibition in xenografts of pancreatic cancer 125 , a treatment strategy currently investigated in a phase I clinical trial 126 . Finally, dinaciclib treatment may be efficacious in MYC-overexpressing triple-negative breast cancers and MYC-driven B-cell lymphomas since it caused tumour regression and enhanced survival in preclinical mouse models 68, 127 .…”

Section: Targeting Cdks In Cancer Therapymentioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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Preface Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins; therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrated that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. In contrast, many cancers are uniquely dependent on these proteins and are hence selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. Here, we review the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as future therapeutic potential of various inhibitors. We focus only on proteins that directly regulate cell cycle progression. Cyclin-dependent kinases with transcriptional functions, as well as PARP inhibitors, which are highly successful in targeting BRCA1/BRCA2-mutant tumours, are not covered by this review.

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Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models

Cited by 53 publications

References 60 publications

Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition

Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 and AKT Inhibition

HEATR1 Negatively Regulates Akt to Help Sensitize Pancreatic Cancer Cells to Chemotherapy

Cell cycle proteins as promising targets in cancer therapy

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