Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities

Franco, Jorge; Balaji, Uthra; Freinkman, Elizaveta; Witkiewicz, Agnieszka K.; Knudsen, Erik S.

doi:10.1016/j.celrep.2015.12.094

Cited by 168 publications

(170 citation statements)

References 52 publications

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“…Interestingly, we have shown that in addition to cell cycle inhibition, palbociclib also suppresses the activity of mTOR’s downstream mediators, p70S6K and S6, likely potentiating the metabolic effects. In line with previous studies (38), we demonstrated that palbociclib activates mTOR—which is likely due to feedback mechanisms from suppression of mTOR downstream mediators, of cellular metabolism, and of the cell cycle. Contrasting with our results, a recent report on palbociclib-induced metabolic reprogramming in Ras-mutated pancreatic cancer (38) showed that palbociclib treatment activated both glycolytic and mitochondrial metabolism through mTOR activation.…”

Section: Discussionsupporting

confidence: 92%

“…In line with previous studies (38), we demonstrated that palbociclib activates mTOR—which is likely due to feedback mechanisms from suppression of mTOR downstream mediators, of cellular metabolism, and of the cell cycle. Contrasting with our results, a recent report on palbociclib-induced metabolic reprogramming in Ras-mutated pancreatic cancer (38) showed that palbociclib treatment activated both glycolytic and mitochondrial metabolism through mTOR activation. These differences could be due to the presence of Ras mutation in the pancreatic cancer model or to the different tissue contexts.…”

Section: Discussionsupporting

confidence: 92%

“…Our findings have shown that combining CDK4/6 and mTOR inhibitors offers increased benefits against GBM through a number of mechanisms—including blockade of compensatory signaling mechanisms, improved brain penetration of palbociclib, enhanced metabolic effects, and cytostatic to cytotoxic conversion. A few recent reports have identified benefit in combining CDK4/6 and Akt or mTOR inhibition in other cancers (38,39), but these have been in different contexts and did not identify the biologic rationales noted here.…”

Section: Discussionmentioning

confidence: 81%

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Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Olmez

Brenneman

Xiao

et al. 2017

Clinical Cancer Research

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Purpose Glioblastoma (GBM) is a deadly brain tumor marked by dysregulated signaling and aberrant cell cycle control. Molecular analyses have identified that the CDK4/6-Rb-E2F axis is dysregulated in about 80% of GBMs. Single-agent CDK4/6 inhibitors have failed to provide durable responses in GBM, suggesting a need to combine them with other agents. We investigate the efficacy of the combination of CDK4/6 inhibition and mTOR inhibition against GBM. Experimental Design Preclinical in vitro and in vivo assays using primary GBM cell lines were performed. Results We show that the CDK4/6 inhibitor palbociclib suppresses the activity of downstream mediators of the mTOR pathway, leading to rebound mTOR activation that can be blocked by the mTOR inhibitor everolimus. We further show that mTOR inhibition with everolimus leads to activation of the Ras mediator Erk that is reversible with palbociclib. The combined treatment strongly disrupts GBM metabolism, resulting in significant apoptosis. Further increasing the utility of the combination for brain cancers, everolimus significantly increases the brain concentration of palbociclib. Conclusions Our findings demonstrate that the combination of CDK4/6 and mTOR inhibition has therapeutic potential against GBM and suggest it should be evaluated in a clinical trial.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 81%

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Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Olmez

Brenneman

Xiao

et al. 2017

Clinical Cancer Research

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“…45 Tumor cell arrest during the G1/S transition, by inhibitors of Cdk4/6, is one of the new avenues for breast carcinoma treatment. 46 While such treatment successfully reduces tumor size, it may also accumulate reactive oxygen species and increase Cyclin D1 expression, 47 which have been linked to increased migration and invasion. 48,49 Hence, understanding of the coordination between cell cycle and cell migration, as well as the other hallmarks of metastasis is increasingly important.…”

Section: Discussionmentioning

confidence: 99%

Directed, but not random, breast cancer cell migration is faster in the G1 phase of the cell cycle in 2D and 3D environments

et al. 2018

Preprint

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Cancer cell migration is essential for the early steps of metastasis, during which cancer cells move through the primary tumor and reach the blood vessels. In vivo, cancer cells are exposed to directional guidance cues, either soluble, such as gradients of growth factors, or insoluble, such as collagen fiber alignment. Depending on the number and strength of such cues, cells will migrate in a random or directed manner. Interestingly, similar cues also stimulate cell proliferation. In this regard, it is not clear whether cell cycle progression affects migration of cancer cells and whether this effect is different in random versus directed migration. In this study, we tested the effect of cell cycle progression on random and directed migration, both in 2D and 3D environments, in the breast carcinoma cell line, FUCCI-MDA-MB-231, using computational image analysis by LEVER. Directed migration in 2D was modeled as chemotaxis along a gradient of soluble EGF inside 10 µm-wide microchannels. In 3D, directed migration was modeled as contact guidance (alignotaxis) along aligned collagen fibers. Time-lapse recordings of cells in 2D and 3D revealed that directed, but not random migration, is cell cycle-dependent. In both 2D and 3D directed migration, cells in the G1 phase of the cell cycle outperformed cells in the G2 phase in terms of migration persistence and instantaneous velocity. These data suggest that in the presence of guidance cues in vivo, breast carcinoma cells in the G1 phase of the cell cycle may be more efficient in reaching vasculature.not peer-reviewed)

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“…Use of these inhibitors will need to account for potential compensatory responses leading to drug resistance or tumor growth exacerbation. For instance, pharmacologic inhibition of CDK4/6 leads to accumulation of mitochondria and reactive oxygen species (ROS) and activation of mTORC1 signaling in PDA cells, while enhanced cell cycle arrest or cytotoxicity can be achieved with the further addition of inhibitors for MTORC, MEK, BCL2 and/or ROS scavenging [51]. …”

Section: The Molecular Landscape Of Pancreatic Cancer: New Therapeutimentioning

confidence: 99%

Leveraging Mechanisms Governing Pancreatic Tumorigenesis To Reduce Pancreatic Cancer Mortality

Donahue

Dawson

2016

Trends in Endocrinology & Metabolism

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Pancreatic ductal adenocarcinoma (PDA) is a devastating malignancy with limited and modest clinical treatments. High throughput technologies and accurate disease models now provide a comprehensive picture of the diverse molecular signaling pathways and cellular processes governing PDA tumorigenesis. Central among these is oncogenic KRAS, a mediator of cellular plasticity, metabolic reprogramming, and inflammatory and paracrine signaling required for tumor development and maintenance. Biological aggressiveness is further conferred by a highly fibrotic and immunosuppressive PDA microenvironment that also acts as a barrier to effective drug delivery. The regulation of these mechanisms and their implications for early cancer detection, chemoprevention and therapy are discussed.

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Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities

Cited by 168 publications

References 52 publications

Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Directed, but not random, breast cancer cell migration is faster in the G1 phase of the cell cycle in 2D and 3D environments

Leveraging Mechanisms Governing Pancreatic Tumorigenesis To Reduce Pancreatic Cancer Mortality

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