Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma

Lu, Haiquan; Lü, Yang; Xie, Yangyiran; Qiu, Songbo; Li, Xinqun; Fan, Zhen

doi:10.1172/jci.insight.131106

Cited by 26 publications

(27 citation statements)

References 75 publications

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“…PDHK4 has been shown to be upregulated in response to high fat diets and diabetes [ 32 , 33 , 34 , 35 , 36 , 37 ]. It has previously been shown that deregulation of PDH and the pyruvate oxidation pathway are involved in tumor initiation and development of cancer [ 27 , 38 , 39 , 40 ]. In the presented study, we analyzed expression data from NSCLC patient cohorts to elucidate the possible correlation between PDHK1 and genes involved in key metabolic pathways.…”

Section: Introductionmentioning

confidence: 99%

Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells

Dyrstad

Lotsberg

Tan

et al. 2021

Cancers

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Increased glycolytic activity is a hallmark of cancer initiation and progression and is often observed in non-small cell lung cancer (NSCLC). Pyruvate dehydrogenase (PDH) complex acts as a gatekeeper between glycolysis and oxidative phosphorylation, and activation of PDH is known to inhibit glycolytic activity. As part of a standard therapeutic regimen, patients with NSCLC harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) are treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). Independent of good initial response, development of resistance to this therapy is inevitable. In the presented work, we propose that inhibition of glycolysis will add to the therapeutic effects and possibly prevent development of resistance against both EGFR TKIs and ionizing radiation in NSCLC. Analysis of transcriptome data from two independent NSCLC patient cohorts identified increased expression of pyruvate dehydrogenase kinase 1 (PDHK1) as well as upregulated expression of genes involved in glucose metabolism in tumors compared to normal tissue. We established in vitro models of development of resistance to EGFR TKIs to study metabolism and determine if targeting PDHK would prevent development of resistance to EGFR TKIs in NSCLC cells. The PDHK1 inhibitor dichloroacetate (DCA) in combination with EGFR TKIs and/or ionizing radiation was shown to increase the therapeutic effect in our NSCLC cell models. This mechanism was associated with redirected metabolism towards pyruvate oxidation and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Using DCA, the intracellular pool of pyruvate available for lactic fermentation becomes limited. Consequently, pyruvate is redirected to the mitochondria, and reinforces mitochondrial activity. Addition of DCA to cell culture deacidifies the extracellular microenvironment as less lactate is produced and excreted. In our study, we find that this redirection of metabolism adds to the therapeutic effect of EGFR TKI and ionizing radiation in NSCLC.

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Section: Introductionmentioning

confidence: 99%

Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells

Dyrstad

Lotsberg

Tan

et al. 2021

Cancers

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“…Several proteins involved in classic cancer pathways, such as proliferation, apoptosis, invasion, and metastasis, could be altered and implicated in CTX resistance during HNSCC treatment ( 64 , 115 , 161 – 165 ).…”

Section: Mechanisms Of Resistance To Cetuximabmentioning

confidence: 99%

“…As a continuation of their work on the role of hypoxia and glycolysis during HNSCC treatment, Lu et al. explore the role in CTX resistance of the mitochondrial enzyme pyruvate dehydrogenase kinase-1 (PDK1), known to allow the switching glucose metabolism toward aerobic glycolysis in cancer cells ( 165 ). They found that the combination of CTX plus PDK1 knockdown (siRNA) or with pharmacological inhibition of PDK1 with dichloroacetic acid (DCA) overcomes CTX-resistance in vitro and in vivo (xenografts) thanks to the overproduction of reactive oxygen species (ROS) and the subsequent apoptosis.…”

Section: Mechanisms Of Resistance To Cetuximabmentioning

confidence: 99%

Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

et al. 2021

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Head and neck squamous cell carcinoma (HNSCC) is the sixth most incident cancer worldwide. More than half of HNSCC patients experience locoregional or distant relapse to treatment despite aggressive multimodal therapeutic approaches that include surgical resection, radiation therapy, and adjuvant chemotherapy. Before the arrival of immunotherapy, systemic chemotherapy was previously employed as the standard first-line protocol with an association of cisplatin or carboplatin plus 5-fluorouracil plus cetuximab (anti-EFGR antibody). Unfortunately, acquisition of therapy resistance is common in patients with HNSCC and often results in local and distant failure. Despite our better understanding of HNSCC biology, no other molecular-targeted agent has been approved for HNSCC. In this review, we outline the mechanisms of resistance to the therapeutic strategies currently used in HNSCC, discuss combination treatment strategies to overcome them, and summarize the therapeutic regimens that are presently being evaluated in early- and late-phase clinical trials.

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“…In addition to its effects on the mitochondrial membrane potential, DCA is believed to lead to a signi cant increase in reactive oxygen species (ROS) generation, which plays an important role in the induction of apoptosis (10)(11)(12)(13)(14). By contrast, other authors reported that DCA may function as a sensitizer for ROS induced alterations, but did not signi cantly increase ROS production per se (13,15). The DCA dose as well as the metabolic state of the cell may impact DCA-mediated ROS production.…”

Section: Compoundsmentioning

confidence: 99%

Dichloroacetate and PX-478 Exhibit Strong Synergistic Effects in a Various Number of Cancer Cell Lines.

Parczyk

Ruhnau

Pelz

et al. 2020

Preprint

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Background: One key approach for anticancer therapy is drug combination. Drug combinations can help reduce doses and thereby decrease side effects. Further, the likelihood of drug resistance is reduced. Distinct alterations in tumour metabolism have been described in past decades, but metabolism has yet to be targeted in clinical cancer therapy. Recently, we found evidence for a synergism between dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor and HIF1-α inhibitor PX-478. In this study, we aimed to analyse this synergism in cell lines of different cancer types and to identify the underlying biochemical mechanisms.Methods: The dose-dependent antiproliferative effects of the single drugs and their combination were assessed using MTT or SRB assays. FACS, Western blot and HPLC analyses were performed to investigate changes in reactive oxygen species levels, apoptosis and the cell cycle. Additionally, real-time metabolic analyses (Seahorse) were performed with DCA-treated MCF-7 cells.Results: The combination of DCA and PX-478 produced synergistic effects in all eight cancer cell lines tested, including colorectal, lung, breast, cervical, liver and brain cancer. Reactive oxygen species generation and apoptosis played important roles in this synergism. Furthermore, cell proliferation was inhibited by the combination treatment.Conclusions: Here, we found that these cancer metabolism-targeting compounds exhibited potent synergism across all tested cancer cell lines. Thus, we highly recommend the combination of these two compounds for progression to in vivo translational and clinical trials.

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Rational combination with PDK1 inhibition overcomes cetuximab resistance in head and neck squamous cell carcinoma

Cited by 26 publications

References 75 publications

Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells

Blocking Aerobic Glycolysis by Targeting Pyruvate Dehydrogenase Kinase in Combination with EGFR TKI and Ionizing Radiation Increases Therapeutic Effect in Non-Small Cell Lung Cancer Cells

Precision Medicine Approaches to Overcome Resistance to Therapy in Head and Neck Cancers

Dichloroacetate and PX-478 Exhibit Strong Synergistic Effects in a Various Number of Cancer Cell Lines.

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