Effect of early-stage autophagy inhibition in BRAFV600E autophagy-dependent brain tumor cells

Zahedi, Shadi; Fitzwalter, Brent E.; Morin, A; Grob, Sydney; Desmarais, Michele; Nellan, Anandani; Green, Adam L.; Vibhakar, Rajeev; Hankinson, Todd C.; Foreman, Nicholas; Levy, Jean M. Mulcahy

doi:10.1038/s41419-019-1880-y

Cited by 25 publications

(24 citation statements)

References 41 publications

(61 reference statements)

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“…Furthermore, the stage of autophagy inhibition may be of relevance in order to observe increased therapeutic effects of AraC. In other types of cancer, either early stage (e.g., ULK inhibitors) or late stage (e.g., CQ, BafA1) autophagy inhibitors were optimal to observe additive or synergistic effects in combination with cytotoxic drugs [ 31 , 32 , 33 , 34 ]. Thus, it is possible that AML patient cells do respond to other autophagy inhibitors, which is of interest to study in further research.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Visser

Lourens

Huls

et al. 2021

IJMS

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Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Visser

Lourens

Huls

et al. 2021

IJMS

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“…As reported above, BRAF mutations are common in gangliogliomas, pleomorphic xanthoastrocytoma, and cerebral pilocytic astrocytomas [ 98 ]. BRAFV600E mutation has been found to increase the tumours’ reliance on autophagy, thereby increasing their susceptibility to autophagy inhibitors compared to their wild-type counterparts [ 99 , 100 ].…”

Section: Autophagy In Childhood Brain Tumoursmentioning

confidence: 99%

Recent Advances in Understanding the Role of Autophagy in Paediatric Brain Tumours

et al. 2021

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Autophagy is a degradative process occurring in eukaryotic cells to maintain homeostasis and cell survival. After stressful conditions including nutrient deprivation, hypoxia or drugs administration, autophagy is induced to counteract pathways that could lead to cell death. In cancer, autophagy plays a paradoxical role, acting both as tumour suppressor—by cleaning cells from damaged organelles and inhibiting inflammation or, alternatively, by promoting genomic stability and tumour adaptive response—or as a pro-survival mechanism to protect cells from stresses such as chemotherapy. Neural-derived paediatric solid tumours represent a variety of childhood cancers with unique anatomical location, cellular origins, and clinical presentation. These tumours are a leading cause of morbidity and mortality among children and new molecular diagnostics and therapies are necessary for longer survival and reduced morbidity. Here, we review advances in our understanding of how autophagy modulation exhibits antitumor properties in experimental models of paediatric brain tumours, i.e., medulloblastoma (MB), ependymoma (EPN), paediatric low-grade and high-grade gliomas (LGGs, HGGs), atypical teratoid/rhabdoid tumours (ATRTs), and retinoblastoma (RB). We also discuss clinical perspectives to consider how targeting autophagy may be relevant in these specific paediatric tumours.

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“…In addition, despite an initial response, BRAF-driven cancer cells can become resistant to BRAF V600E kinase inhibition. Using early or late autophagy inhibitors (i.e., SBI-0206965, VPS34 knockdown, CQ, ATG5 knockdown and ATG7 knockdown) could overcome acquired resistance to BRAF inhibitors in brain tumor patients [ 50 , 51 ], indicating an important role for autophagy inhibition to prevent drug resistance.…”

Section: Brain Cancermentioning

confidence: 99%

Tumors Responsive to Autophagy-Inhibition: Identification and Biomarkers

Barbeau

Keulers

Rouschop

2020

Cancers

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Recent advances in cancer treatment modalities reveal the limitations of the prevalent “one-size-fits-all” therapies and emphasize the necessity to develop personalized approaches. In this perspective, identification of predictive biomarkers and intrinsic vulnerabilities are an important advancement for further therapeutic strategies. Autophagy is an important lysosomal degradation and recycling pathway that provides energy and macromolecular precursors to maintain cellular homeostasis. Although all cells require autophagy, several genetic and/or cellular changes elevate the dependence of cancer cells on autophagy for their survival and indicates that autophagy inhibition in these tumors could provide a favorable addition to current therapies. In this context, we review the current literature on tumor (sub)types with elevated dependence on autophagy for their survival and highlight an exploitable vulnerability. We provide an inventory of microenvironmental factors, genetic alterations and therapies that may be exploited with autophagy-targeted approaches to improve efficacy of conventional anti-tumor therapies.

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Effect of early-stage autophagy inhibition in BRAFV600E autophagy-dependent brain tumor cells

Cited by 25 publications

References 41 publications

Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Recent Advances in Understanding the Role of Autophagy in Paediatric Brain Tumours

Tumors Responsive to Autophagy-Inhibition: Identification and Biomarkers

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