HDAC inhibition synergizes with ALK inhibitors to overcome resistance in a novel ALK mutated lung adenocarcinoma model

Stockhammer, Paul; Ho, Cassandra; Hegedűs, Luca; Lotz, Gábor; Molnár, Eszter; Bànkfalvi, Àgnes; Herold, Thomas; Kalbourtzis, Stavros; Ploenes, Till; Eberhardt, Wilfried; Schüler, Martin; Aigner, Clemens; Schramm, Alexander; Hegedűs, Balázs

doi:10.1016/j.lungcan.2020.04.002

Cited by 11 publications

(7 citation statements)

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“…All cells used in this study are listed in Appendix Table S3. Patientderived primary KRAS-mutant LUAD cells (PF139, PF563) were established as we recently reported (Stockhammer et al, 2020). Human bronchial epithelial cells BEAS-2B and the isogenic counterparts BEAS-2B-KRAS (expressing KRAS G12V ) were described in our previous study (Langsch et al, 2016).…”

Section: Cell Culture and Reagentsmentioning

confidence: 99%

Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS ‐mutant cancer

et al. 2021

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KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance antiproliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS wild-type cancer cells. Mechanistically, co-targeting FGFR1 and PLK1 upregulates reactive oxygen species (ROS), leading to oxidative stress-activated c-Jun Nterminal kinase (JNK)/p38 pathway and E2F1-induced apoptosis. We further delineate that autophagy protects from PLK1/FGFR1 inhibitor cytotoxicity and that antagonizing the compensation mechanism by clinically approved chloroquine fully realizes the therapeutic potential of PLK1 and FGFR1 targeting therapy, producing potent and durable responses in KRAS-mutant patientderived xenografts and a genetically engineered mouse model of Kras-induced lung adenocarcinoma. These results suggest a previously unappreciated role for FGFR1 and PLK1 in the surveillance of metabolic stress and demonstrate a synergistic drug combination for treating KRAS-mutant cancer.

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Section: Cell Culture and Reagentsmentioning

confidence: 99%

Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS ‐mutant cancer

et al. 2021

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“…All cell lines were obtained from American Type Culture Collection (Manassas, VA, USA), except patient-derived primary LUAD cells PF139 were established as recently reported [ 63 ]. Cells were maintained in the RPMI medium (Cat.…”

Section: Methodsmentioning

confidence: 99%

Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage

Deng

Gao

Trappetti

et al. 2022

Cell. Mol. Life Sci.

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Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of non-small cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) (KP). Here, we show that epithelial-like, tumor-initiating NSCLC cells feature oxidative phosphorylation (OXPHOS) phenotype that is regulated by LDHB-mediated lactate metabolism. We show that silencing of LDHB induces persistent mitochondrial DNA damage, decreases mitochondrial respiratory complex activity and OXPHOS, resulting in reduced levels of mitochondria-dependent metabolites, e.g., TCA intermediates, amino acids, and nucleotides. Inhibition of LDHB dramatically reduced the survival of tumor-initiating cells and sphere formation in vitro, which can be partially restored by nucleotide supplementation. In addition, LDHB silencing reduced tumor initiation and growth of xenograft tumors. Furthermore, we report for the first time that homozygous deletion of LDHB significantly reduced lung tumorigenesis upon the concomitant loss of Tp53 and expression of oncogenic KRAS without considerably affecting the animal’s health status, thereby identifying LDHB as a potential target for NSCLC therapy. In conclusion, our study shows for the first time that LDHB is essential for the maintenance of mitochondrial metabolism, especially nucleotide metabolism, demonstrating that LDHB is crucial for the survival and proliferation of NSCLC tumor-initiating cells and tumorigenesis.

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“… Fukuda et al (2019) showed that pretreatment with the HDAC inhibitor quisinostat downregulates the expression of miR-200c, leading to higher expression of ZEB1 and promoting tumor cell sensitivity to crizotinib. Stockhammer et al (2020) found that the highly resistant PF240-PE tumor cells to crizotinib and alectinib became sensitive to these ALK inhibitors after treatment with vorinostat. Thus, combining therapies using TKIs and HDACs could be an option to increase the effectiveness, and response treatment to increase survival and disease-free survival in lung cancer patients.…”

Section: Classification and Function Of Hdacs In Lung Cancermentioning

confidence: 99%

“…This promotes cell proliferation and inhibits apoptosis in lung cancer (Lei et al, 2017). Another study showed that acetylation of lysine residues at K185 and K201 sites of the C1 member of the aldo-keto reductase Refs (Busser et al, 2010;Mateen et al, 2012;Chen et al, 2013;Nakagawa et al, 2013;Riley et al, 2013;Gray et al, 2014;Lu et al, 2014;Fischer et al, 2015;Lee et al, 2015;Wang L. et al, 2016;Wang et al, 2016b;McLaughlin et al, 2016;Chen J. H. et al, 2017;Tanimoto et al, 2017;Wang et al, 2017;Yu et al, 2017;Briere et al, 2018;Wang L. et al, 2018;Jia et al, 2018;Wei et al, 2018;Sun et al, 2019;Yousafzai et al, 2019;Zhang et al, 2019;Wang W. et al, 2020;Stockhammer et al, 2020;Wu et al, 2020;Yu et al, 2020;Ma et al, 2021;Meng et al, 2021;Xiao et al, 2021).…”

Section: Classification and Function Of Hdacs In Lung Cancermentioning

confidence: 99%

“… Refs ( Busser et al, 2010 ; Mateen et al, 2012 ; Chen et al, 2013 ; Nakagawa et al, 2013 ; Riley et al, 2013 ; Gray et al, 2014 ; Lu et al, 2014 ; Fischer et al, 2015 ; Lee et al, 2015 ; Wang L. et al, 2016 ; Wang et al, 2016b ; McLaughlin et al, 2016 ; Chen J. H. et al, 2017 ; Tanimoto et al, 2017 ; Wang et al, 2017 ; Yu et al, 2017 ; Briere et al, 2018 ; Wang L. et al, 2018 ; Jia et al, 2018 ; Wei et al, 2018 ; Sun et al, 2019 ; Yousafzai et al, 2019 ; Zhang et al, 2019 ; Wang W. et al, 2020 ; Stockhammer et al, 2020 ; Wu et al, 2020 ; Yu et al, 2020 ; Ma et al, 2021 ; Meng et al, 2021 ; Xiao et al, 2021 ). …”

Section: Classification and Function Of Hdacs In Lung Cancerunclassified

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Histone deacetylases modulate resistance to the therapy in lung cancer

et al. 2022

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The acetylation status of histones located in both oncogenes and tumor suppressor genes modulate cancer hallmarks. In lung cancer, changes in the acetylation status are associated with increased cell proliferation, tumor growth, migration, invasion, and metastasis. Histone deacetylases (HDACs) are a group of enzymes that take part in the elimination of acetyl groups from histones. Thus, HDACs regulate the acetylation status of histones. Although several therapies are available to treat lung cancer, many of these fail because of the development of tumor resistance. One mechanism of tumor resistance is the aberrant expression of HDACs. Specific anti-cancer therapies modulate HDACs expression, resulting in chromatin remodeling and epigenetic modification of the expression of a variety of genes. Thus, HDACs are promising therapeutic targets to improve the response to anti-cancer treatments. Besides, natural compounds such as phytochemicals have potent antioxidant and chemopreventive activities. Some of these compounds modulate the deregulated activity of HDACs (e.g. curcumin, apigenin, EGCG, resveratrol, and quercetin). These phytochemicals have been shown to inhibit some of the cancer hallmarks through HDAC modulation. The present review discusses the epigenetic mechanisms by which HDACs contribute to carcinogenesis and resistance of lung cancer cells to anticancer therapies.

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HDAC inhibition synergizes with ALK inhibitors to overcome resistance in a novel ALK mutated lung adenocarcinoma model

Cited by 11 publications

References 50 publications

Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS ‐mutant cancer

Synergistic effects of FGFR1 and PLK1 inhibitors target a metabolic liability in KRAS ‐mutant cancer

Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage

Histone deacetylases modulate resistance to the therapy in lung cancer

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