Autophagy as a therapeutic target in pancreatic cancer

Piffoux, Max; Eriau, Erwan; Cassier, Philippe

doi:10.1038/s41416-020-01039-5

Cited by 121 publications

(97 citation statements)

References 124 publications

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“…In addition, we previously reported that lab-generated MAL3-101 resistant rhabdomyosarcoma cells, which were obtained by long-term dose escalation, could be partially resensitized to MAL3-101 if autophagy was simultaneously inhibited (Sannino et al, 2018). Together, our study supports the importance of monitoring autophagy efficiency in various cancers in parallel to the development of specific autophagy inhibitors that can be administrated alone or in combination with approved secondary therapies (Amaravadi et al, 2011;Chude and Amaravadi, 2017;Piffoux et al, 2020;Rebecca et al, 2019;Shi et al, 2017).…”

Section: Discussionsupporting

confidence: 75%

Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised

Sannino

Yates

Schurdak

et al. 2021

eLife

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AMPK, AMP-activated protein Kinase; AKT, AK strain Transforming serine/threonine kinase; ASNS, asparagine synthetase; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6; BiP, Immunoglobulin Binding Protein; CHOP, C/EBP homologous protein; CQ, chloroquine; DTT, 1,4-Dithiothreitol; EBSS, Earle's balanced salt solution; eIF2α, eukaryotic initiation factor 2 alpha; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum associated degradation; FBS, fetal bovine serum; GCN2, general control non-derepressible 2 factor; GFP, green fluorescent protein; HER2, epidermal growth factor receptor 2; HIF1α, Hypoxia Inducible Factor 1 Subunit Alpha; HRI, heme-regulated inhibitor kinase; Hsp70, heat shock protein 70; IRE1, inositol-required enzyme 1; ISR, integrated stress response; MAL3-101, phenylmethyl 4-[1,1'-biphenyl]-4-yl-1-[6-[[2-(butylamino)-1-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]hexylamino]-6-oxohexyl]-1,2,3,4-tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylate; mTOR, mechanistic Target Of Rapamycin; PBS, phosphate buffered saline; PERK, PKR-like endoplasmic reticulum resident kinase; PI, propidium iodide; PKR, Protein Kinase RNA-activated; RFP, red fluorescent protein; RPPA, Reverse Phase Protein Array; S6K, 70‐kDa ribosomal protein S6 kinase; TNBC, triple negative breast cancer; UPR, unfolded protein response; XbpI, X-box binding protein 1.

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Section: Discussionsupporting

confidence: 75%

Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised

Sannino

Yates

Schurdak

et al. 2021

eLife

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“…Although the role of autophagy seems to be tumour-suppressive in the initial stages of cancer, the hyper-active autophagy-dependent self-cannibalism has serious negative effects in tumour progression in the later stages. Therefore, the downregulation of autophagy by using various drugs (i.e., chloroquine or hydroxychloroquine) might have an important role in cellular survival [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Approach of KRAS Mutant Tumours by the Combination of Pharmacologic Ascorbate and Chloroquine

2021

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The Warburg effect has been considered a potential therapeutic target to fight against cancer progression. In KRAS mutant cells, PKM2 (pyruvate kinase isozyme M2) is hyper-activated, and it induces GLUT1 expression; therefore, KRAS has been closely involved in the initiation of Warburg metabolism. Although mTOR (mammalian target of rapamycin), a well-known inhibitor of autophagy-dependent survival in physiological conditions, is also activated in KRAS mutants, many recent studies have revealed that autophagy becomes hyper-active in KRAS mutant cancer cells. In the present study, a mathematical model was built containing the main elements of the regulatory network in KRAS mutant cancer cells to explore the further possible therapeutic strategies. Our dynamical analysis suggests that the downregulation of KRAS, mTOR and autophagy are crucial in anti-cancer therapy. PKM2 has been assumed to be the key switch in the stress response mechanism. We predicted that the addition of both pharmacologic ascorbate and chloroquine is able to block both KRAS and mTOR pathways: in this case, no GLUT1 expression is observed, meanwhile autophagy, essential for KRAS mutant cancer cells, is blocked. Corresponding to our system biological analysis, this combined pharmacologic ascorbate and chloroquine treatment in KRAS mutant cancers might be a therapeutic approach in anti-cancer therapies.

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“…PC is a solid tumor with a highly malignant behavior, which has become the fourth largest cancer causing cancer-related death in western countries, with a 5 years survival rate of less than 10% (Siegel et al, 2019). Accumulated evidence showed that autophagy got involved in tumor development and treatment resistance in PC (Piffoux et al, 2020). Thus, it is essential to screen autophagy-related molecular to identify effective prognostic biomarkers for PC.…”

Section: Discussionmentioning

confidence: 99%

A Novel Autophagy-Related IncRNAs Signature for Prognostic Prediction and Clinical Value in Patients With Pancreatic Cancer

Deng

Shi

et al. 2020

Front. Cell Dev. Biol.

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Autophagy is an important bioprocess throughout the occurrence and development of cancer. However, the role of autophagy-related lncRNAs in pancreatic cancer (PC) remains obscure. In the study, we identified the autophagy-related lncRNAs (ARlncRNAs) and divided the PC patients from The Cancer Genome Atlas into training and validation set. Firstly, we constructed a signature in the training set by the least absolute shrinkage and selection operator penalized cox regression analysis and the multivariate cox regression analysis. Then, we validated the independent prognostic role of the risk signature in both training and validation set with survival analysis, receiver operating characteristic analysis, and Cox regression. The nomogram was established to demonstrate the predictive power of the signature. Moreover, high risk scores were significantly correlated to worse outcomes and severe clinical characteristics. The Pearson’s analysis between risk scores with immune cells infiltration, tumor mutation burden, and the expression level of chemotherapy target molecules indicated that the signature could predict efficacy of immunotherapy and targeted therapy. Next, we constructed an lncRNA–miRNA–mRNA regulatory network and identified several potential small molecule drugs in the Connectivity Map (CMap). What’s more, quantitative real-time PCR (qRT-PCR) analysis showed that serum LINC01559 could serve as a diagnostic biomarker. In vitro analysis showed inhibition of LINC01559 suppressed PC cell proliferation, migration, and invasion. Additionally, silencing LINC01559 suppressed gemcitabine-induced autophagy and promoted the sensitivity of PC cells to gemcitabine. In conclusion, we identified a novel ARlncRNAs signature with valuable clinical utility for reliable prognostic prediction and personalized treatment of PC patients. And inhibition of LINC01559 might be a novel strategy to overcome chemoresistance.

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Autophagy as a therapeutic target in pancreatic cancer

Cited by 121 publications

References 124 publications

Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised

Unique integrated stress response sensors regulate cancer cell susceptibility when Hsp70 activity is compromised

Therapeutic Approach of KRAS Mutant Tumours by the Combination of Pharmacologic Ascorbate and Chloroquine

A Novel Autophagy-Related IncRNAs Signature for Prognostic Prediction and Clinical Value in Patients With Pancreatic Cancer

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