miR-147b-mediated TCA cycle dysfunction and pseudohypoxia initiate drug tolerance to EGFR inhibitors in lung adenocarcinoma

Zhang, Wen Cai; Wells, Julie; Chow, Kin-Hoe; Huang, He; Yuan, Min; Saxena, Tanvi; Melnick, Mary Ann; Politi, Katerina; Asara, John M.; Costa, Daniel B.; Bult, Carol J.; Slack, Frank J.

doi:10.1038/s42255-019-0052-9

Cited by 62 publications

(76 citation statements)

References 77 publications

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“…In agreement with a recent tandem mass spectrometry study performed by Zhang and colleagues, we nd that DCA does not increase glucose metabolism, but rather affects pyruvate and lactate metabolism directly [113]. On the level of mRNA, we nd LDHA to be signi cantly downregulated upon 48 h of DCA treatment, further indicating decrease in fermentation.…”

Section: Discussionsupporting

confidence: 92%

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

Dyrstad¹,

Lotsberg²,

Tan³

et al. 2020

Preprint

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Background Non-small cell lung cancer (NSCLC) patients harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) inevitably develop resistance to targeted therapy. Drug resistance is an example of cancer cell plasticity where cells change according to diverse microenvironmental pressure, which can be described as a way of evolution by natural selection. Metabolic rewiring during cancer development may support several malignant features and facilitate emergence of therapy resistant clones. Results Analysis of transcriptome data from two independent NSLSC patient cohorts identified upregulated markers of glucose metabolism and ROS defense in tumors compared to normal tissue. We show that these alterations were associated with increased expression of pyruvate dehydrogenase kinase 1 (PDK1). We established relevant in vitro models to study metabolic alterations in the context of resistance to EGFR TKIs to determine if targeted metabolic intervention would prevent development of resistance to EGFR tyrosine kinase inhibitors (EGFR TKIs) in NSCLC cells. The PDK inhibitor dichloroacetate (DCA) was shown to reduce cell growth. This mechanism was associated with redirected metabolism towards pyruvate and lactate oxidation, and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Conclusion We propose that the intracellular stress created by redirecting pyruvate metabolism can prevent EGFR TKI resistance in NSCLC.

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Section: Discussionsupporting

confidence: 92%

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

Dyrstad¹,

Lotsberg²,

Tan³

et al. 2020

Preprint

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“…In cancer research, miRNAs have been discovered to have a role in developing drug tolerance. Altered miR-147b initiates a reversible state of tolerance to osimertinib in lung cancer cells by binding SDHD (Zhang et al, 2019). Pretreatment with a miR-147b inhibitor delayed osimertinib-associated drug tolerance, providing a promising target for preventing tumor relapse (Zhang et al, 2019).…”

Section: Tca Cyclementioning

confidence: 99%

ncRNAs: New Players in Mitochondrial Health and Disease?

Gusic

2020

Front. Genet.

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The regulation of mitochondrial proteome is unique in that its components have origins in both mitochondria and nucleus. With the development of OMICS technologies, emerging evidence indicates an interaction between mitochondria and nucleus based not only on the proteins but also on the non-coding RNAs (ncRNAs). It is now accepted that large parts of the non-coding genome are transcribed into various ncRNA species. Although their characterization has been a hot topic in recent years, the function of the majority remains unknown. Recently, ncRNA species microRNA (miRNA) and long-non coding RNAs (lncRNA) have been gaining attention as direct or indirect modulators of the mitochondrial proteome homeostasis. These ncRNA can impact mitochondria indirectly by affecting transcripts encoding for mitochondrial proteins in the cytoplasm. Furthermore, reports of mitochondria-localized miRNAs, termed mitomiRs, and lncRNAs directly regulating mitochondrial gene expression suggest the import of RNA to mitochondria, but also transcription from the mitochondrial genome. Interestingly, ncRNAs have been also shown to hide small open reading frames (sORFs) encoding for small functional peptides termed micropeptides, with several examples reported with a role in mitochondria. In this review, we provide a literature overview on ncRNAs and micropeptides found to be associated with mitochondrial biology in the context of both health and disease. Although reported, small study overlap and rare replications by other groups make the presence, transport, and role of ncRNA in mitochondria an attractive, but still challenging subject. Finally, we touch the topic of their potential as prognosis markers and therapeutic targets.

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“…We report here that miR-147b expression increases with TGF- treatment, attenuates KMT2D expression, and subsequently allows the cancer cells to acquire a mesenchymal phenotype. Others have also reported the pro-tumor role of miR-147b [37][38][39] . For example, miR-147b increases the tumorigenicity in hepatocellular carcinoma by targeting ubiquitinconjugating enzyme E2N 37 .…”

Section: Discussionmentioning

confidence: 95%

“…In patients with hepatitis C-associated diffuse large Bcell lymphoma, high miR-147b level is correlated with poor prognosis 38 . Recent work in lung cancer showed that miR-147b endows enhanced drug resistance by altering tricarboxylic acid cycle 39 . These findings suggest the possibility of using miR-147b as a therapeutic target for multiple tumor types.…”

Section: Discussionmentioning

confidence: 99%

KMT2D links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

Kim

Cao

et al. 2020

Preprint

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Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to posttranscriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a non-canonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the pro-tumoral role of KMT2D. These findings reveal a tumor-suppressive role of KMT2D and identify miR-147b and activin A as novel therapeutic targets in pancreatic cancer.

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miR-147b-mediated TCA cycle dysfunction and pseudohypoxia initiate drug tolerance to EGFR inhibitors in lung adenocarcinoma

Cited by 62 publications

References 77 publications

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

Inhibition of pyruvate dehydrogenase kinase redirects NSCLC cell metabolism and counteracts development of resistance to epidermal growth factor receptor tyrosine kinase inhibitors

ncRNAs: New Players in Mitochondrial Health and Disease?

KMT2D links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

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