Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib

Dyczynski, Matheus; Yu, Yasmin; Otrocka, Magdalena; Parpal, Santiago; Braga, Tiago; Henley, Aine Brigette; Zazzi, Henric; Lerner, Mikael; Wennerberg, Krister; Viklund, Jenny; Martinsson, Jessica; Grandér, Dan; Milito, Angelo De; Tamm, Katja Pokrovskaja

doi:10.1016/j.canlet.2018.07.028

Cited by 88 publications

(87 citation statements)

References 72 publications

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“…In particular, breast cancer pathway is highly enriched in targets of autophagy inhibitors (p-value = 1.95e-5) but not activators or dual-modulators. This is consistent with the observation that autophagy inhibitors such as SB02024 increase the sensitivity of breast cancer cells to chemotherapy [81].…”

Section: Functional Analysis Of the Targets Reveals Enriched Pathwayssupporting

confidence: 92%

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Shi

Pei

Perlmutter

et al. 2020

Preprint

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Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g. artenimol and olanzapine acting as activator, fostamatinib as inhibitor, or melatonin as dual-modulator), as well as selected drugs uniquely targeting specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulates the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker bridging between various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.

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Section: Functional Analysis Of the Targets Reveals Enriched Pathwayssupporting

confidence: 92%

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Shi

Pei

Perlmutter

et al. 2020

Preprint

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“…It remains to be determined how the multiple posttranslational modifications of the distinct subunits 198 may affect the composition and function of the Vps34 complexes. Highly-selective Vps34 inhibitors have helped define the various cellular functions and uncovered new biological roles for Vps34 in cancer 208,236,237 and metabolic sensitization 204,208 . Further studies are required to define the biological roles of the distinct Vps34 complexes, and development of complex-specific modulators would certainly help to address this fundamental question but also open opportunities for more refined interference with Vps34 function in disease, such as to selectively interfere with autophagy in cancer 238 .…”

Section: Discussionmentioning

confidence: 99%

PI3K isoforms in cell signalling and vesicle trafficking

Bilanges

Posor

Vanhaesebroeck

2019

Nat Rev Mol Cell Biol

370

364

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Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that phosphorylate intracellular inositol lipids to regulate signalling and intracellular vesicular traffic. Mammals have eight isoforms of PI3K, divided into three classes. The class I PI3Ks generate 3-phosphoinositide lipids which directly activate signal transduction pathways. In addition to being frequently genetically-activated in cancer, similar mutations in class I PI3Ks have now also been found in a human non-malignant overgrowth syndrome and a primary immune disorder which predisposes to lymphoma. The class II and III PI3Ks are regulators of membrane traffic along the endocytic route, in endosomal recycling and autophagy, with an indirect impact on cell signalling. Here we summarize current knowledge on the different PI3K classes and isoforms, focusing on recently uncovered biological functions and the mechanisms by which these kinases are stimulated. Areas covered include emerging evidence for isoform-specific regulation and function of Akt family members, potential non-cytotoxic actions of PI3K inhibitors in cancer and regulation of mTORC1 by class II and III PI3Ks. A deeper insight into the PI3K isoforms will undoubtedly continue to contribute to a better understanding of fundamental cell biological processes, and ultimately, in human disease. The cDNA cloning of the first catalytic subunit of a PI3K (p110, Ref. 1) in 1992 revealed close sequence similarity to the Saccharomyces cerevisiae Vps34 gene product, which was soon thereafter documented to possess PI3K activity in that it could convert phosphatidylinositol (PI) to its 3phosphorylated PI(3)P derivative 2. Subsequent bioinformatic and molecular biology approaches based on sequence homology of the kinase domain of these enzymes allowed the isolation of multiple PI3K genes from a range of organisms, with the Waterfield group proposing the now generally-accepted classification of the isoforms of PI3K 3-6. The main role of Vps34 in yeast in regulating the transport of proteins to the lysosome-like vacuole 7 indicates that regulation of vesicular traffic is the most ancient function of 3-phosphoinositides, with a role in signalling being a later addition in eukaryotic evolution 8. Genetic and pharmacological approaches have now uncovered the broad functions of the different PI3K isoforms, some of which are targets of the first approved PI3K inhibitors for the treatment of human cancer. The challenges faced in effectively targeting PI3K in disease have illustrated that much remains to be learned about PI3K biology. In this review, we summarize key recent insights into PI3K signalling and cell biology in mammals, for example, newly discovered human syndromes, resulting from constitutive activation of class I PI3Ks leading to tissue overgrowth 9 or immune deregulation 10, 11. Despite having been discovered over two decades ago 12, 13 , the class II PI3Ks remain the most enigmatic PI3K subfamily. Recent studies have started to uncover mechanisms by which these PI3Ks are regulated and how t...

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“…Numerous potent and specific VPS34 inhibitors have been reported, including SAR405 (85,144,145) and compound 13 (146). Recently, SB02024, developed by Sprint Biosciences, was reported as a highly potent VPS34 inhibitor with a favorable pharmacokinetic profile and an excellent selectivity toward the kinome that makes it suitable for further profiling toward a clinical candidate (147).…”

Section: Vps34 Inhibitorsmentioning

confidence: 99%

Targeting Autophagy in Cancer: Recent Advances and Future Directions

2019

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Autophagy, a multistep lysosomal degradation pathway that supports nutrient recycling and metabolic adaptation, has been implicated as a process that regulates cancer. Although autophagy induction may limit the development of tumors, evidence in mouse models demonstrates that autophagy inhibition can limit the growth of established tumors and improve response to cancer therapeutics. Certain cancer genotypes may be especially prone to autophagy inhibition. Different strategies for autophagy modulation may be needed depending on the cancer context. Here, we review new advances in the molecular control of autophagy, the role of selective autophagy in cancer, and the role of autophagy within the tumor microenvironment and tumor immunity. We also highlight clinical efforts to repurpose lysosomal inhibitors, such as hydroxychloroquine, as anticancer agents that block autophagy, as well as the development of more potent and specifi c autophagy inhibitors for cancer treatment, and review future directions for autophagy research. Signifi cance: Autophagy plays a complex role in cancer, but autophagy inhibition may be an effective therapeutic strategy in advanced cancer. A deeper understanding of autophagy within the tumor microenvironment has enabled the development of novel inhibitors and clinical trial strategies. Challenges and opportunities remain to identify patients most likely to benefi t from this approach.

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Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib

Cited by 88 publications

References 72 publications

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

PI3K isoforms in cell signalling and vesicle trafficking

Targeting Autophagy in Cancer: Recent Advances and Future Directions

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